Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](NC(=N)O)([CH3:4])([CH3:3])[CH3:2].[NH:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:10]([C:12]([OH:14])=[O:13])[CH3:11]>>[NH:9]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:10]([C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH3:11]
Reactant: CC(C)(C)NC(=N)O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Reaction of 1 at room temperature with 400 mol % of tert-butanol and 1-2 mol % of freshly prepared CuCl gave a quantitative yield of analytically pure tert-butyl isourea 2 (R=But) in less than 1 h. The reaction was monitored using IR by following the disappearance of the carbodiimide absorption at 2130 cm-1 and the appearance of the isourea absorbance at 1660 cm-1. No purification other than evaporation of the excess tert-butanol was necessary to obtain the pure material. Isourea 2 (R=BUt) was then stirred with N-CBZ-Ala (10) in several solvents under a variety of reaction conditions to determine the most effective conditions for tert-butyl ester formation. In general, all the solvents examined gave reasonable yields of N-CBZ-Ala-OBut (15), but warm toluene, overnight, produced the best results. Several other N-BOC protected amino acids were treated with 2 (R=But) and gave good yields of tert-butyl esters under similar conditions. In each example, the yields were comparable if not slightly superior to those obtained using DIC. Esterification of the racemization sensitive CBZ-Ala-Phe (11) with 2 (R=But) gave the tert-butyl ester 20, shown by HPLC analysis to be a single diastereomer. Esterification of 11 using K2CO3 and tert-butyl bromide in DMA (Chevallet et al., Tetrahedron Lett., 34, p. 7409 (1993)) gave 20 with 2.5% racemization to the L,D diastereomer. Other isourea derivatives 2 (R=Bn, Pr1, Et Me) of 1 were synthesized, with results identical to that of 2 (R=But). Each isourea was formed rapidly and quantitatively at room temperature with 1-2 mole % CuCl and only a slight excess of alcohol. The quality of the CuCl catalyst was important, as older samples gave slower reactions and were required in up to 5 mol %. Surprisingly, each isourea, including the But, could be produced quantitatively without the use of catalytic CuCl, although heating and longer reaction times were required. In the case of DIC, no isourea was obtained without catalytic CuCl. All our results indicated that the presence or absence of the CuCl had no effect on esterifications.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:41][C:42]([F:62])([F:61])[C:43]1[CH:44]=[C:45]([S:49]([N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]2[C:58]([OH:60])=O)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1.[NH2:63][C@@H:64]([CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)/[CH:65]=[N:66]/[C:67]1[C:68]([NH:73][CH3:74])=[CH:69][CH:70]=[CH:71][CH:72]=1>C(Cl)Cl>[CH2:75]([C@H:64]([NH:63][C:58]([C@@H:53]1[CH2:54][CH2:55][CH2:56][CH2:57][N:52]1[S:49]([C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([C:42]([F:41])([F:61])[F:62])[CH:44]=1)(=[O:50])=[O:51])=[O:60])/[CH:65]=[N:66]/[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[NH:73][CH3:74])[C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1
Reactant: CNc1ccccc1/N=C/[C@@H](N)Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1ccccc1/N=C/[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
PyBOP (0.11 g, 0.22 mmoles) and triethylamine (0.076 mL, 0.55 mmoles) were added to a room temperature solution of (S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (0.074 g, 0.22 mmol) in CH2Cl2 (5 mL). After stirring at room temperature for 20 min, a solution of N-[(S)-2-amino-3-phenyl-prop-(E)-ylidene]-N′-methyl-benzene-1,2-diamine (0.052 g, 0.22 mmoles) in CH2Cl2 (5 mL) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give a yellow oil. Purification of the residue by flash chromatography on silica gel, eluting with 10-50% EtOAc/heptane afforded 0.078 g (64%) of the title compound as a colorless powder: ES+ LC/MS m/e 557 (M+H), RT=2.92 min; 1H NMR CDCl3: δ9.99 (bd s, 1), 8.05 (s, 1), 7.94 (d, 1, J=8.0 Hz), 7.83 (d, 1, J=7.9 Hz), 7.62 (t, 1, J=7.9 Hz), 7.23-7.56 (m, 8), 7.00 (d, 1, J=7.5 Hz), 5.45 (m, 1), 4.40 (bd s, 1), 3.72 (dd, 1, J=14.5, 5.1 Hz), 3.54 (d, 1, J=14.1 Hz), 3.44 (dd, 1, J=14.5, 10.8 Hz), 2.13-2.26 (m, 2), 1.37 (m, 1), 1.22 (m, 1), 0.92-1.10 (m, 4).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[C:11]([CH3:12])=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]2=[N:7][CH:8]=1)[NH2:2].O.NN.[CH:36](OCC)(OCC)OCC>>[CH3:12][C:11]1[C:5]2[N:4]3[CH:36]=[N:2][N:1]=[C:3]3[CH:8]=[N:7][C:6]=2[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:10]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:24])[O:20][CH2:21][CH2:22][O:23]2)=[CH:15][CH:14]=1
Reactant: Cc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(NN)nc12
Reactant: CCOC(OCC)OCC
Agent: NN
Solvent: O
Product: Cc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc3nncn3c12
Temperature: 100 °C
Yield: 60 %

Procedure:
To a flask was added 2-hydrazinyl-7-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.357 g, 0.784 mmol, prepared using O from Preparation #20 with hydrazine hydrate) in triethyl orthoformate (3.91 mL, 23.5 mmol). The mixture was heated to about 100° C. for about 20 h. The mixture was concentrated in vacuo to give a residue. The residue was loaded directly on a silica gel column and eluted with 0 to 8% MeOH/DCM to provide 8-methyl-7-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.220 g, 60%): LC/MS (Table 2, Method g) Rt=1.66 min; MS m/z 466 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[C:4]2[C:6]=1[C:15](=[O:14])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][NH:5]2
Reactant: COc1ccc(OC)c(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(OC)ccc(OC)c2c1=O

Procedure:
Ethyl 5,8-dimethoxy-3-quinolinecarboxylate was formed as described in the literature (E. H. Erickson, C. F. Hainline, L. S. Lenon, et al. J. Med. Chem. 1979, 22, 816). 2,5-Dimethoxyaniline and diethyl ethoxymethylenemalonate condense and then cyclise at high temperature (250° ) in diphenyl ether to form ethyl 1,4-dihydro-5,8-dimethoxy-4-oxo-3-quinolinecarboxylate which is chlorinated at the 4-position with phosphorus oxychloride to give ethyl 4-chloro-5,8-dimethoxy-3-quinolinecarboxylate. The dehalogenation of this quinoline (20.34 g, 0.069 mol) in 150 ml of absolute ethanol with 1 g of 5% Pd/C and 22.53 ml of triethylamine (0.156 mol) was done with a Parr hydrogenator apparatus which gave the correct product, ethyl 5,8-dimethoxy-3-quinolinecarboxylate, as well as the 1,4-dihydro and the 1,2,3,4-tetrahydro quinoline products. This result of further reduction to the 1,4-dihydro product was indicated in the article listed above on page 817, but the formation of the 1,2,3,4-tetrahydro product had not been mentioned there. These three quinoline products were separated on a silica gel column which was eluted with hexane, followed by hexane:ethyl acetate/4:1 and 1:1, giving 0.46 g (2.6% yield) of the title compound, NMR: CDCl3 δ1.23 (tr, 3, CH2Me), 2.94 (br-m, 2, CH2), 3.2-3.6 (m, 3, CH2, CH), 3.76 (s, 6, (OMe)2), 4.21 (quartet, 2, CH2Me), 4.2 (br, 1, NH), 6.12 (d, 1, Ar), 6.57 (d, 1, Ar); 3.31 g of the 1,4-dihydro quinoline product (18.5%), NMR: CDCl3 δ 1.28 (tr, 3, CH2Me), 3.61 (s, 2, CH2), 3.73 (s, 6, (OMe)2), 4.19 (quartet, 2, CH2Me), 6.2-6.7 (br, 1, NH), 6.29 (d, 1, Ar), 6.60 (d, 1, Ar), 7.32 (d, 1, pyr-H); and 2.04 g (11%) of the ethyl 5,8-dimethoxy-3-quinolinecarboxylate.
Reaction SMILES: C([O:3][C:4](=[O:32])[NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:14]=2)[CH2:8]1)C.[CH3:33][CH2:34]OCC.[ClH:38]>C(Cl)Cl>[ClH:38].[CH2:33]([N:5]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:14]=2)[CH2:8]1)[C:4](=[O:32])[OH:3])[CH3:34]
Reactant: CCOCC
Reactant: CCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Agent: Cl
Solvent: ClCCl
Product: CCN(C[C@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1)C(=O)O

Procedure:
To a solution of ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (89 mg, 0.2 mmol) in 2 mL CH2Cl2 under an N2 atmosphere was added ether (10 mL) followed by the dropwise addition of a 2.0 M solution of HCl in ether (0.1 mL, 0.2 mmol) which resulted in precipitation of ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride which was then filtered and dried (85 mg, 90%). LC/MS: m/z 439.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 7.45 (m, 2H), 6.81 (m, 2H), 4.57 (m, 2H), 3.89 (m, 2H), 3.52 (m, 1H), 3.36 (m, 1H), 2.95 (s, 2H), 2.52 (s, 3H), 1.86 (m, 3H), 1.66 (m, 1H), 1.39 (m, 1H), 1.07 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH2:23]1.Cl.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([N:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=4)[CH2:23][CH:22]3[CH2:21][O:20][CH3:19])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)OCCC(C(=O)Cl)=C2
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2OCC1
Reaction time: 0.5 h

Procedure:
A solution of 7,8-dimethoxy-2,3-dihydro-1-benzoxepine-4-carbonyl chloride (300 mg) in dichloromethane (10 ml) is added dropwise, taking 30 minutes under ice-cooling while stirring, to a mixture of 3-methoxymethyl-1-(3,4,5-trimethoxybenzoyl)piperazine×hydrochloride (400 mg) obtained in Reference Example 6, triethylamine (1 ml) and dichloromethane (30 ml). The reaction mixture is washed with an aqueous solution of citric acid and an aqueous solution of sodium hydrogencarbonate, then dried over magnesium sulfate, followed by concentration. The concentrate is subjected to a silica gel column chromatography (eluent: ethyl acetate-methanol =95:5) to afford 1-(7,8-dimethoxy2,3-dihydro-1-benzoxepin-4-ylcarbonyl) -2-methoxymethyl4-(3,4,5-trimethoxybenzoyl)piperazine (520 mg) as colorless crystals, m.p. 142° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[C:13]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([C:17]1[N:22]=[C:21]([NH:23][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=2[C:9]([O:11][CH3:12])=[O:10])[CH:20]=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: CC(C)(C)c1cccc(N)n1
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C)n1
Temperature: 130 °C
Yield: 34.8 %

Procedure:
A mixture of methyl 4,6-dichloropyridazine-3-carboxylate (0.69 g, 3.33 mmol) and 6-tert-butylpyridin-2-amine (1.00 g, 6.67 mmol) was dissolved in acetonitrile (3 mL) and heated at 130° C. for 14 h The dark brown mixture was cooled, concentrated onto silica, and purified by chromatography (silica, 80 g, 0-20% acetone in dichloromethane, 40 min) to give methyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (372 mg, 1.16 mmol, 35%) as a yellow solid. MS (EI/CI) m/z: 321.0 [M+H].
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:13]2[NH:14][C:15]([C:17]3[C:18](=[O:33])[NH:19][CH:20]=[CH:21][C:22]=3[NH:23][CH2:24][C@@H:25]([OH:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:36]>C1COCC1>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][C:35](=[O:36])[NH:7][C:8]2[C:13]3[NH:14][C:15]([C:17]4[C:18](=[O:33])[NH:19][CH:20]=[CH:21][C:22]=4[NH:23][CH2:24][C@@H:25]([OH:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:39][CH:40]=1
Reactant: Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(OC(=O)Nc2cccc3nc(-c4c(NC[C@@H](O)c5ccccc5)cc[nH]c4=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
Pyridine (2.0 ml) was added to a solution of 3-(7-amino-1H-benzoimidazol-2-yl)-4-((S)-2-hydroxy-2-phenyl-ethylamino)-1H-pyridin-2-one (0.060 g, 0.166 mmol) (Prepared according to the general method for the intermediates of formula II and III above) and 4-methoxyphenyl chloroformate (0.062 g, 0.32 mmol) in THF (2 ml) and the reaction stirred at room temperature. After 20 hours the reaction was concentrated and the crude mixture was purified by column chromatography (1-2% methanol, dichloromethane) to give the desired product (0.028 g; 33%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.Br[CH2:14][CH2:15][CH2:16]Br>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:16][CH2:15][CH2:14]2)[CH:2]=1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: BrCCCBr
Product: CCOC(=O)C1(c2cccnc2)CCC1

Procedure:
Prepared in a similar manner to that described above by reacting ethyl 2-pyridin-3-ylacetate with 1,3-dibromopropane to give ethyl 1-pyridin-3-ylcyclobutane-1-carboxylate which was then hydrogenated to give the desired compound as a brown oil (quantitative reaction).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:26]1([C:32]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=4[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:24][CH3:25])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC(=O)N4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (intermediate 4) (86 mg), morpholine-4-carbonyl chloride (114 mg), and potassium carbonate (175 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (17 mg, yield 15%).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][OH:18])[CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][OH:18])[CH2:9]1)=[O:27])[CH3:30]
Reactant: OCc1cccc2c1CN(Cc1ccccc1)C2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1Cc2cccc(CO)c2C1
Yield: 66.7 %

Procedure:
To a mixture of 5.27 g of 2-benzyl-4-hydroxymethylisoindoline and 2.43 g of sodium carbonate in 25 ml of chloroform was added dropwise 2.49 g of ethyl chloroformate under ice-cooling while stirring. After stirring for 2 days at room temperature, the mixture was washed with water and concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol =10/1) to obtain 3.25 g of 2-ethoxycarbonyl-4-hydroxymethylisoindoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:40][C:38]1[CH:39]=[C:34]([CH3:33])[N:35]=[C:36]([C:41]2([NH:44][C:26]([C:25]3[C:24]([O:30][CH3:31])=[CH:23][C:22]([CH3:32])=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=3)=[O:27])[CH2:42][CH2:43]2)[N:37]=1
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.17 g, 0.1 mmol, 3 eq) (60% purity), HOBT (0.046 g, 0.34 mmol, 1.0 eq), EDC.HCl (0.072 g, 0.37 mmol, 1.1 g) in DCM at ambient temperature under a nitrogen atmosphere was added diisopropylethylamine (0.132 g, 1.0 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.44 (d, J=3.36 Hz, 2H), 1.51-1.54 (d, J=3.48 Hz, 2H), 2.32-2.34 (d, J=5.8 Hz, 9H), 2.81-2.82 (d, J=4.6 Hz, 3H), 4.0 (s, 3H) 7.0 (s, 1H), 7.15 (s, 1H), 7.34-7.42 (m, 3H), 7.52 (s, 1H), 7.72-7.74 (d, J=8.8 Hz, 2H), 7.97-8.02 (m, 2H), 8.46-8.48 (d, J=4.56 Hz, 1H), 8.91 (s, 1H). LCMS: (ES+) m/z=579.2 (M+H)+
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].Br[C:13]1C(C)=CC=CC=1N>>[ClH:1].[Br:2][C:3]1[C:8]([CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][NH2:11]
Reactant: Cc1cccc(N)c1Br
Reactant: Cc1ccc(NN)c(Br)c1
Agent: Cl
Product: Cc1cccc(NN)c1Br

Procedure:
2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 2-bromo-3-methylaniline as starting material.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[NH2:21][CH2:22][CH2:23][CH2:24][Si:25]([O:36][Si:37]([CH3:40])([CH3:39])[CH3:38])([O:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[O:26][Si:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O>[CH3:8][Si:7]([CH3:10])([CH3:9])[O:6][Si:5]([CH2:4][CH2:3][CH2:2][N:21]([CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:19])([CH3:18])[CH3:20])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:8])([CH3:9])[CH3:10])[CH2:22][CH2:23][CH2:24][Si:25]([O:36][Si:37]([CH3:39])([CH3:38])[CH3:40])([O:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[O:31][Si:32]([CH3:35])([CH3:34])[CH3:33])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[O:11][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)O[Si](CCCN)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C[Si](C)(C)O[Si](CCCI)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)O[Si](CCCN(CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 80 °C
Reaction time: 15 h

Procedure:
14.3 g of 3-iodopropyltris(trimethylsiloxy)silane (28), 5.7 g of 3-aminopropyltris(trimethyl-siloxy)silane and 9.6 g of sodium carbonate are added to 50 ml dimethylacetamide and stirred for 15 hours at 80° C. The dimethylacetamide is then evaporated and the residue taken up in methylene chloride. The organic phase is washed with water, dried and evaporated. The product is purified by column chromatography on silica gel to give 7 g of a slightly yellowish oil of formula (30); 1H-NMR (ppm, CDCl3): 2.21 6H t, 1.38 6H txt, 0.28 6H t, 0 81H s.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)[CH:2]=C.[BH4-].[Na+].C[OH:17]>C1COCC1>[OH:17][CH2:2][CH2:1][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: C=CCc1ccc2c(c1)COC2=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCc2cc(CCO)ccc21
Temperature: -78 °C

Procedure:
5-(Prop-2-en-1-yl)-2-benzofuran-1(3H)-one (1.53 g, 8.78 mmol) was dissolved in a mixture of methanol (30 mL) with just enough THF to solubilize the starting material and was cooled to −78° C. Ozone was bubbled through the solution until the reaction mixture color changed (to orange). Then nitrogen gas was bubbled through the reaction mixture for about one min. to remove the residual ozone. Sodium borohydride (0.65 g, 17 mmol) was added and the mixture was allowed to warm to room temperature. The reaction mixture was partially concentrated then was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over MgSO4. The crude product was purified by MPLC (silica) eluting with ethyl acetate to afford pure product. LCMS: m/z 179 (M+1)+; 1H NMR (500 MHz, CD3OD) δ 7.77 (m, 1H), 7.37-7.41 (m, 2H), 5.23 (s, 2H), 192 (m, 2H), 2.99 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>[Pd].C(O)C>[N:12]1([CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1CCN1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCN1CCOCC1
Yield: 77.3 %

Procedure:
4-[(2-Nitrophenyl)ethyl]morpholine (11.4 g, 40 mmol) and palladium on carbon (10%, 500 mg) in ethanol (200 ml) were hydrogenated under 1 Atm. of hydrogen at room temperature for 3 h. The reaction was filtered through hyflo and the filtrate reduced to dryness under vacuum. The residue was recrystallized from toluene/hexane to give 2-(2-morpholin-4-ylethyl)aniline (6.375 g). Microanalysis: calculated C 69.87, H 8.80, N 13.58; found C 69.80; H, 8.95; N, 13.60.