Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]C1(C(OC(C)(C)C)=O)CC1.[CH:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.BrCCCCBr.[Li+].CC([N-]C(C)C)C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Reactant: CCCCOC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: BrCCCCBr
Product: CCCCOC(=O)C1(CCCCBr)CCCC1

Procedure:
Compound 103c was prepared, likewise the procedure described for 103b, starting from butyl cyclopentanecarboxylate (Payne, G. B. et al. J. Org. Chem., 1957, 22, 1680-1682) (80.0 g, 0.42 mol), 1,4-dibromobutane (183.3 g, 0.84 mol) and LDA (2 M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) to give, after purification by fractional distillation under reduced pressure, 103c (62.8 g, 49%) as a light yellow liquid. bp: T=116-117° C. (p=0.040-0.051 Torr). 1H NMR: δ 4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). 13C NMR: δ 177.6, 64.1, 53.9, 38.2, 36.0 (2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6. HRMS calcd for C14H25BrO2 (M+): 304.1038. found: 304.1042.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CNCCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)CCl
Temperature: 25 °C
Yield: 94.5 %

Procedure:
At −75° C., chloroacetyl chloride (11.3 g, 8.1 mL, 0.1 mol) was added slowly to a suspension of methyl-phenethyl-amine (13.5 g, 0.1 mol), triethylamine (15 mL) in dichloromethane (50 mL). The suspension was warmed to 25° C. over the course of 3 hours and the salt was removed by filtration. The organic phase was washed with HCl solution (1 N, 200 mL), dried with sodium sulfate. The solvent was evaporated in vacuo to give 2-chloro-N-methyl-N-phenethyl-acetamide (20 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.2 (m, 5H), 4.03 (s, 3H), 3.6 (m, 2H), 2.99 (s, 2H), 2.8 (m, 2H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:29])[C@H:8]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:38][CH2:39][S:40](Cl)(=[O:42])=[O:41].C(Cl)(Cl)Cl>ClCCl>[C:2]([O:6][C:7](=[O:29])[C@H:8]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][S:40]([CH:39]=[CH2:38])(=[O:42])=[O:41])=[CH:13][CH:12]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=CS(=O)(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
4-(aminomethyl)benzoyl-glutamic acid di-t-butyl ester hydrochloride as obtained in Reference Example 37 (255 mg) and triethylamine (0.27 ml) were dissolved in dichloromethane (4 ml). To this solution, a solution of chloroethylsulfonyl chloride (161 mg) in dichloromethane (4 ml) was added drop by drop under ice cooling conditions over a period of about 15 minutes, followed by stirring at the same ternperature for 30 minutes. To the mixture, ice water (12 ml). and chloroform (10 ml) were added, followed by vigorous stirring, after which the organic layer was separated, and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol:chloroform=1:99) to yield the title compound (172 mg, yield 58.3%) as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH2:25]([CH2:27][NH2:28])[OH:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][NH:28][CH2:27][CH2:25][OH:26])=[CH:19]2)=[N:2]1
Reactant: NCCO
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: OCCNCc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with ethanolamine (35 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 187 (24 mg, 35%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][OH:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 88.8 %

Procedure:
A solution 58.0 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester, 45.0 g of (1,1-dimethylethyl)dimethylsilylchloride, 69 ml of triethylamine, 1.50 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride is stirred at room temperature for 18 hours. The resulting solution is washed with water, 2N hydrochloric acid, saturated sodium bicarbonate and sodium chloride. The organic layer is dried and concentrated in vacuo. The residue, dissolved in methylene chloride, is filtered through a silica gel pad and concentrated in vacuo to give 76.5 g of the desired product as a colorless oil. [α]D26° =-46° (methylene chloride).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:46]2[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=2)[CH2:49][Cl:50])[CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43]>>[ClH:50].[ClH:50].[ClH:50].[CH2:1]([N:8]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:13][CH2:14]1)[CH2:49][C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([C:38]2[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:36]([O:35][CH3:34])[CH:37]=2)[CH:47]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(NCc4ccccc4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(Cc3ccccc3)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC
Product: Cl

Procedure:
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: Cl.[F:2][CH:3]([F:14])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[OH:13].C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[NH:28][C:27](=O)/[C:26]/2=[CH:35]/OC>CN(C)C=O>[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[N:28][CH2:27]/[C:26]/2=[CH:35]\[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH:3]([F:14])[F:2])=[C:6]([OH:13])[CH:7]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1ccc(OC(F)F)c(O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cc(CN/C=C2\CN=Cc3ccc(I)cc32)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
An amount of 4-difluoromethoxy-3-hydroxy benzylamine hydrochloride (113 mg, 0.50 mmol), is dissolved in N,N-dimethylformamide (5 mL), triethylamine (50 μL 0.75 mmol) is added followed by (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (165 mg, 0.50 mmol). After the mixture is stirred at room temperature for 30 min, the solvent is removed in-vacuo and the residue dissolved in 7.5% methanol in chloroform and passed thru a short pad of Florisil eluting with 7.5% methanol in chloroform, the eluate is evaporated and the solid triturated with ether, filtered and washed several times with anhydrous ether to give 193 mg of (4Z)-6-Iodo-4-{[(4-difluoromethoxy-3-hydroxybenzyl)amino)methylene}isoquinoline-1,3(2H,4-dione as a beige solid (79% yield); mp 254-5° C., MS data ES(−) 485.0 m/e.
Reaction SMILES: [C:1]1([C@H:7]([OH:26])[CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[C:1]1([C@H:7]([OH:26])[CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline (2.5 g, 7.0 mmole) in CH2Cl2 (15 mL) was cooled in an ice bath under stream of nitrogen and TFA (15 mL) was slowly added. The reaction mixture was stirred for 2 h at 0° C. and then concentrated in vacuo. The crude product was dissolved in 20% MeCN/H2O and purified by preparative reversed phase HPLC (5 to 2% MeCN/H2O over 50 min; 254 nm; 20 mL/min.), to give N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate salt 31 as a colorless oil. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm); 7.45-7.25 (m, 9H), 4.9 (dd, 1H), 3.55-3.45 (m, 2H), 3.21-3.15 (t, 2H), 3.05-2.95 (t, 2H) ESMS (C16H20N2O1): calcd. 256.4, obsd. 257.1 [M+H]+, 280.2 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.0 g, 8.4 mmole) and ethyl 2-bromopropanoate (1.52 g, 8.4 mmole) in tetrahydrofuran (50 ml) was added triethylamine (0.85 g, 8.4 mmole) The mixture was stirred at room temperature for 20 hours. Solids were removed by filtration and the filtrate was added to diethyl ether (75 ml) and then washed with 1 N hydrochloric acid (50 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].O.NN>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:13])[CH2:10][O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 87.7 %

Procedure:
To a solution of 196 (2.0 g, 5.7 mmol) and THF:MeOH (1:1, 20 mL) at RT was added hydrazine monohydrate (2.9 g, 57 mmol) and the reaction was heated to 50° C. for 18 h. The reaction was cooled to RT, filtered, and the filtrate was poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:30) to afford 1.1 g (88%) of (S)-1-(3,4-dichlorophenyl)-2-methoxyethanamine as a off-white solid (198).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[OH-].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CC(=O)C(Cc2ccc(Cl)cc2)C(=O)C1
Temperature: 59 °C
Reaction time: 2.75 h
Yield: 42 %

Procedure:
449 g (3.21 mols) dimedone (5,5-dimethylcyclohexane-1,3-dione) were added to a solution of aqueous potassium hydroxide comprising 166 g of 85% potassium hydroxide (2.52 mols) in 700 ml of water. The mixture was then warmed and a clear orange solution was obtained at 47° C. The solution was then heated to 59° C. and 544 g (3.21 mols) molten 4-chlorobenzyl chloride were added over a period of 1 hour with further heating to 85° C. Heating was continued for a further 2.5 to 3 hours up to a temperature of 100° C. The mixture was then cooled, the solid product filtered off, washed with water and dried in a vacuum oven at 50° C. The crude solid (815 g) was then dissolved in 2,400 ml methanol at reflux and 200 ml water added to produce a permanent cloudiness. The mixture was then allowed to cool to room temperature overnight with stirring. The solid so obtained was filtered, washed with about 400 ml cold methanol and dried in a vacuum oven to produce 340 g 2-(4-chlorobenzyl)-5,5-dimethylcyclohexane-1,3-dione as a white solid, m.pt. 188°-190° C. Yield: 42%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:39][C:40](O)=[O:41])[CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:30].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:40](=[O:41])[CH2:39][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (290 mg, 1.08 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (502 mg, 1.05 mmol) in DMF (7 mL) was added Et3N (250 μl, 1.79 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3—MeOH (40:1, v/v) as an eluent to give 550 mg (93%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) d 1.11-1.18 (m, 3 H), 1.37-1.41 (m, 3 H), 2.30 (s, 3 H), 3.47-3.53 (m, 2 H), 3.61-3.75 (m, 7 H), 3.84 (s, 3 H), 4.03-4.27 (m, 2 H), 4.33-4.39 (m, 2 H), 6.34-8.07 (series of m, total 12 H).
Reaction SMILES: [CH2:1]([C:4]1([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:7][CH2:6][CH2:5]1)C=C.O.CC([OH:21])(C)C.C[N+]1([O-])[CH2:28][CH2:27][O:26]CC1.S([O-])([O-])=O.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.O>[Si:9]([O:8][C:4]1([CH2:1][CH:27]([OH:26])[CH2:28][OH:21])[CH2:7][CH2:6][CH2:5]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C=CCC1(O[Si](C)(C)C(C)(C)C)CCC1
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1(CC(O)CO)CCC1
Reaction time: 0.08 h

Procedure:
To a 2 L round bottomed flask was added (1-allylcyclobutoxy) (tert-butyl)dimethylsilane (previous step) and H2O/t-BuOH (1:1, 1 L). NMO (32.68 g, 279 mmol) was added to the mixture. After stirring for 5 min the solution was found to be homogenous. Osmium tetroxide (1.00 g, 3.93 mmol) was added and the reaction was stirred at RT. After 2 h, TLC revealed the reaction to be complete. 500 mL of H2O and sodium sulfite (19.5 g, 155 mmol) were added and the reaction was stirred for another hour. The aqueous solution was extracted with ether (2×1 L). The combined organics were concentrated in vacuo to give 3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol, as a light yellow oil. The oil contained some t-BuOH, but was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]COC)=[C:15]([O:23][CH3:24])[CH:14]=3)=[C:10]([S:25][CH3:26])[C:9]=2[CH:27]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:27][C:9]=3[C:10]=2[S:25][CH3:26])[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: COCCc1ccc2oc(-c3ccc(OCOC)c(OC)c3)c(SC)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COCCc1ccc2oc(-c3ccc(O)c(OC)c3)c(SC)c2c1
Reaction time: 0.67 h

Procedure:
The solution containing 590 mg of 5-(2-methoxy-ethyl)-2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran (14a; 1.52 mM) dissolved in 8 ml of dichloromethane was cooled to 0□. 4.0 ml of trifluoroacetic acid was added thereto and stirred for 40 mins at 0□. 7.5 g of solid sodium hydrogen carbonate and 60 ml of water were added thereto slowly at 0□. The reaction mixture was extracted with dichloromethane. The organic solvent layer was dried with magnesium sulfuric acid, filtrated and the filtrate was concentrated with vaccuo.
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:22][N:21]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH:3]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CCCCCN1CC(C(=O)OC(C)(C)C)=C(O)C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCN1CC(C(=O)OC(C)(C)C)C(=NO)C1=O
Reaction time: 36 h
Yield: 89.2 %

Procedure:
To a mechanically stirred solution of the title compound of Example F (17.5 g, 0.065 mol) in 60 ml of pyridine was added hydroxylamine hydrochloride (5.41 g, 0.078 mol) and resulting solution was stirred for 36 h. Evaporation of the solvent afforded a light yellow oil which was chromatographed on silica gel eluting with 3% EtOH/CH2Cl2 to give the title compound (16.48 g, 89%) as a white solid: Anal calcd for C14H24N2O4 : C, 59.14, H, 8.51; N, 9.85. Found C, 58.91; H, 8.48; N, 9.71. MS calcd for C14H24N2O4 284, found 284. DSC=131.0°-134.7° C. at 93.1 J/g.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.O1CCCC1.[Br:29]N1C(=O)CCC1=O>>[Br:29][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[N:19]2[C:14]=1[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]2
Reactant: CSc1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Into a 30 mL vial, 7-(4-Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.205 g, 0.000642 mol), Methanol (4 mL, 0.1 mol) and Tetrahydrofuran (9 mL, 0.1 mol) were added. N-Bromosuccinimide (0.137 g, 0.000770 mol) was added portion wise over 5 minutes. The reaction was stirred at room temperature over night. The solvent was removed under vacuum. The solid was partitioned with water and filtered to give a yellow solid. The solid was washed with cold methanol to give 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (140 mg, 55%). NMR 1H (DSMO-d6)-9.01 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.07 (d, 2H, J=8.53 Hz), 7.79 (s, 1H), 3.28 (s, 3H), 2.62 (s, 3H)
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:40][C:41]1[C:48]2[C:47]([CH3:49])=[CH:46][S:45][C:44]=2[S:43][C:42]=1[CH2:50][NH:51][CH3:52].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:51]([CH2:50][C:42]2[S:43][C:44]3[S:45][CH:46]=[C:47]([CH3:49])[C:48]=3[C:41]=2[CH3:40])[CH3:52])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CNCc1sc2scc(C)c2c1C
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1csc2sc(CN(C)C(=O)/C=C/c3cnc(N)c(CN4CCOCC4)c3)c(C)c12

Procedure:
According the procedure of Example 1, except substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (3,4-dimethyl-thieno[2,3-b]thiophen-2-ylmethyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound was prepared (70 mg, 13%) as a light, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.40 (s, 1H), 7.51 (d, J=15.1 Hz, 1H), 7.20-7.12 (m 2H), 5.00-4.77 (m, 2H), 4.40-4.32 (m, 2H), 3.95-3.15 (m, 10H), 3.13 (s, 3H), 2.90 (s, 1H), 2.46 (s, 3H), 2.45 (s, 3H); MS (ESI) m/e 457 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[OH:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:21]2[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(CCCO)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CCCO)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanol (37.9 mmol), tert-butyl 2-iodobenzoate (11.5 g, 37.9 mmol), sodium carbonate (10 g, 94.8 mmol), 1,1′-bis(diphenylphosphino)ferroncene-palladium dichloride dichloromethane complex (1:1), DMF (170 mL) and water (22 mL) was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to RT, poured into water, and the product was extracted with EtOAc-Hexanes (1:1). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated, and the residue was purified on silica gel (Hexane/EtOAc, from 2/1 to 1/1) to afford tert-butyl 4′-(3-hydroxypropyl)biphenyl-2-carboxylate.