Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:23])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.[CH:24](=O)[CH3:25].C([BH3-])#N.[Na+].Cl>CO>[Cl:23][C:7]1[C:6]2[C:2]([NH:1][CH2:24][CH3:25])=[N:3][NH:4][C:5]=2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[N:8]=1
Reactant: CC=O
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.5 %

Procedure:
To a stirred solution of (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (0.06 g, 0.18 mmol) in methanol (2.0 mL) was added aqueous acetaldehyde (0.025 mL, 35 wt. % in water, 0.20 mmol) followed by sodium cyanoborohydride (0.03 g, 0.54 mmol) and stirred at room temperature for 12 h. After confirming the completion of reaction by TLC, the reaction mixture was acidified with 1.5 N HCl and concentrated under reduced pressure. The crude product was dissolved in ethyl acetate, washed with 10% NaOH followed by water and brine solution. The organic layer was concentrated under reduced pressure and crude product was purified by preparative HPLC to afford (R)-1-(4-chloro-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (0.021 g, 32.0%). 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.05 (s, 1H), 7.44 (s, 1H), 7.37-7.32 (m, 4H), 7.26-7.22 (m, 2H), 5.44 (t, J=5.6 Hz, 1H), 4.84 (m, 1H), 3.28-3.23 (m, 2H), 1.39 (d, J=8.00 Hz, 3H), 1.20 (t, J=6.8 Hz, 3H). MS ES calc'd. for C17H19ClN6O2 [M+H]+ 359. Found: 359.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][CH2:21][C:20](=O)[C:19]=2[CH:24]=1.O>C1COCC1>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH2:5][C:3]#[N:4])=[CH:20][C:19]=2[CH:24]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1ccc2c(c1)C(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2oc(CC#N)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
Reaction under N2 atmosphere. NaH 60% (0.17 mol) was stirred in TBF (350 ml). A solution of diethyl (cyanomethyl)phosphonate (0.17 mol) in THF (150 ml) was added dropwise over ±20 minutes. (exothermic temperature rise to 30° C.). The mixture was stirred for 20 minutes at RT, then cooled to 0° C. A solution of 5-methyl-3-benzo-furanone (0.15 mol) in THF (350 ml) was added dropwise over 30 minutes at 0° C. reaction mixture was stirred overnight at RT, then poured out into water (1500 ml) and stirred. This mixture was extracted with ether, DIPE (2×), dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 50/50). The desired fractions were collected and the solvent was evaporated, yielding 21.2 g (82%) of 5-methyl-3-benzofuranacetonitrile (interm. 3).
Reaction SMILES: [Cl:1]Cl.[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[K]>>[Cl:1][N:7]1[C:3](=[O:13])[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:5]2[C:6]1=[O:8]
Reactant: ClCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 91 %

Procedure:
Chlorine gas was bubbled into one liter of methylene chloride maintained at 0° C. The chlorine was added for about 10 minutes and until saturation was achieved. To the resulting chlorine-saturated methylene chloride were added 50 grams (270 mmoles) of potassium phthalimide as a solid and in one portion. The resulting mixture was allowed to warm gradually to 20° C., and additional chlorine was introduced as a gas during two separate periods to ensure the presence of an excess of chlorine. The mixture then was stirred vigorously at 20° C. for 60-90 minutes. The resulting precipitated potassium chloride was removed by filtration, and the filtrate was evaporated in vacuo to dryness. The residual white solid was suspended in 150 ml. of water for a few minutes, filtered, and washed with 100 ml. of water. The solid was vacuum dried overnight to obtain 44.5 grams (91% yield) of N-chlorophthalimide.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])/[C:28](/[CH3:36])=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])/[C:28](/[CH3:36])=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: C/C(=C\c1ccccc1)C(=O)NCCN=[N+]=[N-]
Product: C/C(=C\c1ccccc1)C(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.1103 g, 0.397 mmol) was reacted with (E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide (0.092 g, 0.397 mmol) following the general click procedure to give (E)-tert-butyl 2-amino-4-(5-(1-(2-(2-methyl-3-phenylacrylamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 7H), δ 6.94 (s, 2H), 6.06 (s, 2H), δ 4.46 (s, 2H), δ 3.79 (s, 2H), δ 2.61 (s, 2H), δ 2.27 (s, 2H), δ 1.99 (s, 3H), δ 1.49 (bs, 11H), δ 1.18 (s, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 192.4, 191.3, 170.4, 150.9, 140.2, 136.2, 134.8, 131.6, 129.6, 128.6, 128.1, 122.1, 95.8, 85.2, 74.3, 53.7, 52.6, 50.7, 49.4, 40.1, 29.9, 29.3, 28.9, 28.2, 25.6, 14.4 ppm; HRMS (ESI) calcd for C27H37N7O3 (M+) 507.2958. found 507.2942, which was subsequently deprotected to give (E)-N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-methyl-3-phenylacrylamide hydrochloride (0.148 g, 84% yield). 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), δ 7.33 (s, 4H), δ 7.26 (s, 1H), δ 7.19 (s, 1H), δ 6.42 (s, 1H), δ 4.78 (s, 2H), δ 3.84 (s, 2H), δ 2.87 (s, 2H), δ 2.44 (s, 2H), δ 1.99 (s, 3H), δ 1.76 (s, 2H), δ 1.59 (s, 2H), δ 1.42 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 174.7, 136.0, 134.4, 131.5, 129.3, 128.7, 128.3, 128.0, 127.6, 108.6, 94.6, 53.1, 39.2, 27.6, 27.9, 27.7, 27.6, 24.1, 23.8, 23.1, 14.3, 13.4 ppm; HRMS (ESI) calcd for C22H29N7O (M+) 407.2434. found 407.2429.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCCCBr)cc1

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4-hydroxybenzonitrile and 1,3-dibromopropane.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[CH:31]([NH:34][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:2])([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Product: CC(C)NC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid isopropylamide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester and isopropylamine in an analogous manner to example 12. MS calcd. for C26H36N3O3[(M+H)+] 438.0, obsd. 437.8.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.[Cl-].[NH4+]>C(OCC)C.C([Li])CCC>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:21])([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a solution of 3-bromopyridine (640 mg) in diethyl ether (10 ml), n-butyl lithium (2.5M-hexane solution, 1.80 ml) was added at −74° C. After 15 minutes' stirring at the same temperature, a solution of ethyl 2-(4-chlorophenyl)-2-oxoacetate (960 mg) in diethyl ether (100 ml) was added. The temperature of the system was raised to room temperature over 30 minutes, and to the reaction solution saturated aqueous ammonium chloride solution was added and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=3/2) to provide ethyl 2-(4-chlorophenyl)-2-hydroxy-2-(3-pyridinyl)acetate (571 mg) as a yellow oily substance.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22](O)=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:22]([C:19]1[S:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:10]3[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=3)[C:13]=2[C:20]=1[CH3:21])=[O:23]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)C)c12
Reactant: CN(C)CCCN
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3OC(C)C)c12

Procedure:
Prepared analogously to example 1.3 using 4-(2-isopropoxypyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (descirbed in 1.2) and 3-dimethylaminopropylamine. The resultant product was purified by chromatography.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.B.[CH3:41]O>C1COCC1>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:41][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: CO
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of Compound B (150 mg, 0.42 mmol) in THF (10 mL) was added borane (1 M in THF, 3 mL, 3 mmol). The solution was refluxed for 3 h and cooled to room temperature. Methanol (5 mL) was added and the solution was concentrated. 5 N HCl (10 mL) was added and the mixture was refluxed for 4 h, cooled to room temperature, neutralized to pH 6 with 50% NaOH and extracted with methylene chloride (3×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and concentrated to yield compound C as a slightly yellow glass (70 mg, 50%). MS (M+H)+ 330.
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:15][CH:14]=1)(=[O:12])[NH2:11].CO.C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][C:10]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:25][CH:26]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(=O)c1ccc(OCCn2ccnc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1ccc(OCCn2ccnc2)cc1)c1ccccc1

Procedure:
Treatment of benzoic acid with N,N'-carbonyldiimidazole and 1-[2-(4-carbamoylphenoxy)ethyl]imidazole in dry N,N-dimethylformamide as described in Example 34 gave 1-[2-(4-benzoylcarbamoylphenoxy)ethyl]imidazole, m.p. 152°-154° C. (from methanol/ethyl acetate). Found: C, 67.66; H, 5.16; N, 12.59. C19H17N3O3 requires: C, 68.05; H, 5.11; N, 12.53%.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:53].[OH-].[Na+]>O.C(O)(=O)C.ClCCCl>[ClH:53].[ClH:53].[ClH:53].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][CH2:37][NH:38][CH2:1][C:3]2[C:12]3[O:11][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=3[CH:6]=[CH:5][CH:4]=2)[CH2:33][CH2:34]1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Reactant: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CCCNCc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 0.53 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 0.55 g of 3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine, 70 ml of 1,2-dichloroethane and 0.11 ml of acetic acid was added 0.64 g of sodium triacetoxyborohydride. The mixture was stirred at room temperature for 4.5 hours. The reaction mixture was poured into 100 ml of water and acidified with 37% hydrochloric acid. This was followed addition of cold 6N aqueous sodium hydroxide to make the solution alkaline. The mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, (in vacuo) the residue was purified by flash chromatography on silica gel eluting with chloroform/methanol (100:5). The fractions containing the pure base were combined and the solvent was evaporated to dryness. The title compound, obtained as a base, was converted in the usual manner into the trihydrochloride salt, and crystallized from ethanol, m.p. 170°-176° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)=O)=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[NH4+:34].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:34]=[C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)cc1
Temperature: 150 °C
Yield: 89.4 %

Procedure:
A mixture of N-[2-(4-chlorophenyl)-2-oxoethyl]-4-(phenylmethyl)-2-morpholinecarboxamide (3.3 g, 8.85 mmol) and ammonium trifluoroacetate (5.27 g, 44.3 mmol) was heated at 150° C. for 20 minutes. After cooling, to the resulting mixture was added water (50 mL) and CH2Cl2 (50 mL). The organic layer was separated and washed with brine, dried (MgSO4), and concentrated to afford the crude title compound (2.8 g). LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-]>CC(C)=O>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:12])=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[NH2:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C)c(C(=O)O)c1N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C)c(C(=O)OCc2ccccc2)c1N
Yield: 47.6 %

Procedure:
A mixture of 940 mg (5.73 mmol) of 2-amino-3,6-dimethylbenzoic acid, 0.750 ml (6.3 mmol) of benzyl bromide, 1.04 g (7.5mmole) of potassium carbonate and 40 mg (0.27mmole) of soium iodide in 20 ml of acetone was heated to reflux for 20 hr. The resulting mixture was then concentrated in vacuo and the residue was chronatoghed with EtOAc/Hexane (1:50) as eluant to provide 697 mg (48%) of the desired product as a yellow oil. Electrospray Mass Spec 256 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:20][NH2:21])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2c1CC(=NN)c1ccccc1S2

Procedure:
0.9g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin and 1g of 100% hydrazine hydrate were dissolved in 10ml of ethanol and the resulting mixture was heated under reflux for 3.5 hours. The reaction mixutre was concentrated to 5ml to separate crystals on cooling, which were collected by filtration. Recrystallization from ethanol afforded 0.6g of 9-cyano-10,11-dihydro-11-oxo-dibenzo-[b,f]thiepin hydrazone as pale brown prismatic crystals having a melting point of 175°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:36])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:30])[C:11]=2[CH2:31][O:32]C(=O)C)=[CH:8][CH:9]=1)=[O:4]>N.CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:36])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:30])[C:11]=2[CH2:31][OH:32])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)n1C
Agent: N
Solvent: CO
Product: COC(=O)c1ccc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)n1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.3 %

Procedure:
A mixture of 5-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (237 mg, 0.486 mmol) in saturated NH3/MeOH (20 mL) was stirred at room temperature for 48 h. The mixture was evaporated to dryness to give 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (150 mg, yield 68%) as a yellow solid. LC-MS calcd for C26H27N3O4 (m/e) 445.20, obsd 913 [2M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.C(N(CC)CC)C.[CH3:60][N:61](C)[CH:62]=[O:63]>>[Br:13][C:11]1[C:10]([CH2:14][O:15][CH:16]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][CH2:2][NH:1][C:62]([NH:61][CH3:60])=[O:63])[CH:5]=[C:6]2[CH3:52]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)NCCn1cc(C)c2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c(Br)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 0.270 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 76b) in 1.5 ml of N,N-dimethylformamide is cooled to 0° C. and admixed successively with 0.066 g of N-succinimidyl N-methyl carbamate and 0.043 ml of triethylamine. The reaction mixture is stirred at room temperature over 2 hours, subsequently poured onto water (40 ml) and extracted with dichloromethane (2×40 ml). The organic phases are washed successively with water (40 ml), 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (2:1 EtOAc-heptane); Rt=5.76.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:34])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:34])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(F)c1)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 26.1 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile (2.2 g, 8 mmol) prepared in Example 65a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 26%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(CO)CC2(C1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)CC2(C1)OCCO2
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 7,9-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]decane (6.3 g, 21 mmol) in dry dichloromethane (100 ml) with triethylamine (8.90 ml, 63.8 mmol) was added methanesulfonyl chloride (4.11 ml, 53.2 mmol) drop-wise at 0° C. The reaction was allowed to come to ambient temperature and stir overnight. The reaction was quenched with saturated sodium bicarbonate (50 ml) and allowed to stir for 15 min. After separation, the aqueous layer was extracted with dichloromethane (1×50 ml). The combined extracts were dried over potassium carbonate, filtered and concentrated to give a dark brown liquid (7.3 g, 97%).