Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cn2cc(Cl)ccc2n1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)c3cn4cc(Cl)ccc4n3)CC2)cc1
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid (0.170 g) and 1-(4-methoxyphenyl)piperazine (Aldrich; 0.165 g) in dichloromethane (4 mL) are added diethyl cyanophosphonate (Aldrich; 0.157 mL) and triethylamine (0.144 mL), followed by DMF (2 mL). After stirring overnight, the mixture is quenched with aqueous sodium bicarbonate and then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are filtered through sodium sulfate and concentrated, and the residue is chromatographed on silica gel using methanol/dichloromethane (2/98) to give 0.212 g of 1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)carbonyl]-4-(4-methoxyphenyl)piperazine; mp 180-181° C.: IR (mineral oil) 1620, 1517, 1237, 1246, 1230 cm-1. 1H NMR (CDCl3) δ3.16, 3.78, 3.97, 4.47, 6.86, 6.94, 7.21, 7.56, 8.10,8.20.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=O)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=O)[CH:19]=[N:20][CH:21]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:10]2[C:11](=[O:12])[O:13][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:9]2)[CH:19]=[N:20][CH:21]=1
Reactant: Cc1ccc(C(=O)NCC(=O)O)s1
Reactant: COc1cncc(C=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cncc(C=C2N=C(c3ccc(C)s3)OC2=O)c1
Temperature: 90 °C
Yield: 56.6 %

Procedure:
To a screw-capped test tube, N-[(5-methyl-2-thienyl)carbonyl]glycine (60 mg, 0.3 mmol), 5-methoxy-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 51 mg of the above-captioned compound.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:1]([N:5]([C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)[NH:6][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:18]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)N(N)C(C)(C)C)c1
Reactant: CCc1ccc(C(=O)Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c(F)c1
Reaction time: 8 h

Procedure:
0.150 g of 3,5-dimethyl-benzoic acid N-tert-butyl-hydrazide (1 eq. 0.68 mmol) and 0.110 mL (1.2 eq, 0.77 mmol) of 2-fluoro-4-ethyl benzoyl chloride were weighed into a 1 oz. vial. A small stirbar was added followed by 2 mL of methylene chloride. The mixture was stirred until the hydrazone dissolved. The stirring was stopped and 2 mL of a 1 M potassium carbonate (K2CO3) solution was added. The mixture was allowed to stir overnight. At the end of this period, 1 mL of water and 1 mL of methylene chloride were added. The aqueous phase was removed and the organic phase was washed twice with 1 M potassium carbonate solution. The organic phase was removed and dried over magnesium sulfate. The organic phase was filtered thru a pad of baste alumina and the solvent removed. The product, 3,5-dimethylbenzoic acid N-tert-butyl-N′-(2-fluoro-4-ethylbenzoyl)-hydrazide, was purified by trituration with 1:1 ether:hexane. 1NMR (300 MHz, CDCl3) δ (ppm): 7.7 (m, 2H), 7.6 (t, 1H), 7.0 (m, 3H), 2.6 (q, 2H), 2.3 (s, 3H), 2.1 (s, 6H), 1.5 (s, 9H), 1.1 (t, 3).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:26]2[CH:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccc(Cl)cc5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccc(Cl)cc5)c4)n[nH]c3n2)CC1
Reaction time: 4 h

Procedure:
To a stirred solution of {4-[3-[3-(4-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (120 mg, 0.177 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another four hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give N-{3-[3-(4-chloro-benzylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine as solid. (Yield 25 mg, 31%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[CH:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butylamide (example 278) (0.137 g, 0.24 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.100 g, 81%). MS (ISP) 519.2 [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: [BH3-]C#N
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: NC(c1ccccn1)c1ccccn1

Procedure:
To a solution of di-2-pyridyl ketone (1.84 g, 10 mmol) and ammonium acetate (7.7 g, 100 mmol) in anhydrous methanol (30 ml) was added sodium cyanoborohydride (1.26 g, 20 mmol) and the resulting solution heated at reflux for 5 hours. The reaction mixture was then cooled in an ice bath and acidified to pH 2 with concentrated HCl. Solvent was removed under reduced pressure and the residue dissolved in water (30 ml), washed with ether (3×10 ml) then basified to pH 10 with solid sodium hydroxide. The solution was then extracted with dichloromethane (3×20 ml) and the combined organic phase dried over anhydrous MgSO4, filtered and concentrated to a brown oil (1.6 g, 86%). The crude product was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[OH:1][C:2]([CH2:14][C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)c1ccncc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Product: CCOC(=O)C(O)(CC(=O)c1ccncc1)C(=O)OCC

Procedure:
Diethyl ketomalonate (17.4 g, 0.1 mol) was heated with 4-acetylpyridine (12.1 g, 0.1 mol) at 120° C. for 15 h under nitrogen to provide diethyl 2-hydroxy-2-(4-pyridyl)cabonylmethyl-malonate as a crystalline solid. The diester was refluxed in ethanol with a slight excess of hydrazine hydrate hydrochloride for 15 h to provide 3-hydroxy-6-(4-pyridyl)-4-carbethoxy-pyridazine (4, Scheme 1). The above ester was recrystallized from ethanol, hydrolyzed with aqueous sodium hydroxide followed by careful neutralization with hydrochloric acid to afford 3-hydroxy-6-(4-pyridyl)-pyridazine-4-carboxylic acid (5, Scheme 1). The acid was dissolved in phosphorous oxychloride containing a catalytic amount of DMF and the mixture was allowed to react at 80° C. for 4 h to provide 3-chloro-4-chlorocarbonyl-6-(4-pyridyl)pyridazine (6, Scheme 1) as a dark oil. the above dichloride was treated with gaseous ammonia in acetonitrile to afford the title compound as a tan solid. The above dichloride was treated with excess gaseous ammonia to afford the title compound as a tan solid: 1H NMR (DMSO-d6) δ 8.80 (d, J=6 Hz, 2H), 8.59 (s, 1H), 8.20 (s, 1H), 8.17 (d, 6 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[Br:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1CBr

Procedure:
To 100 mL round bottom flask charged with ester 101b (230 mg, 1.04 mmol), N-bromosuccinimide (214 mg, 1.2 mmol), benzoyl peroxide (25 mg, 0.1 mmol) in benzene (5 mL). After the mixture was stirred at reflux for 4 h, H2O (10 mL) was added. The aqueous phase was extracted with CH2Cl2 (2×10 mL), and the combined organic extracts were washed with brine (10 mL), dried with Na2SO4 and concentrated. The crude 101c (287 mg, 92%) was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([OH:18])([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:23]CCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([O:18][CH3:23])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CCCCCC
Reactant: COC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC1(C(=O)O)CCN(c2ncc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of methyl 1-(5-bromopyrimidin-2-yl)-4-hydroxypiperidine-4-carboxylate (0.2 g, 0.63 mmol) in DMF (25 mL) was cooled to 0° C. followed by portion wise addition of NaH (60% dispersion in mineral oil, 0.05 g, 1.08 mmol) and the mixture stirred at 0° C. for 45 min followed by addition of MeI (0.20 mL, 3.16 mmol). The temperature of the reaction was slowly raised to rt and left to stir for 4 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 3% EtOAc:hexane to obtain the product as an off-white solid (0.12 g, 57% yield). MS: 330.18 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:6]=[N:7][C:2]([N:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)=[CH:3][CH:4]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCOCC4)nc3)cn2)cc1
Yield: 74.3 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.307 mmol) obtained in Step A in Example 1-D-48 and morpholine (40.2 mg, 0.462 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Step B in Example 1-D-48, amination was carried out, to obtain a crude product of bis-(4-methoxy-benzyl)-{5-[2-morpholin-4-yl-7-(6-morpholin-4-yl-pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-amine as a yellow solid (160 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-110) as a yellow powder (56 mg, 53%).
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:13]([OH:16])[CH2:14][OH:15])=O)C1C=CC=CC=1.C(OC(N[C@@H](CC1C=CC=CC=1)[C@H](O)CO)=O)C1C=CC=CC=1>>[OH:15][CH2:14][C@@H:13]1[O:16][C:9](=[O:8])[NH:11][C@@H:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@H](Cc1ccccc1)[C@@H](O)CO)OCc1ccccc1
Agent: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CO)OCc1ccccc1
Product: O=C1N[C@H](Cc2ccccc2)[C@H](CO)O1
Yield: 69.8 %

Procedure:
The reaction procedure of Example 9 was repeated except that 400 mg (1.27 mmols) of (2R,3R)-3-(benzyloxycarbonylamino)-4-phenylbutane-1,2-diol was used in lieu of 400 mg (1.27 mmols) of (2S,3S)-3-(benzyloxycarbonylamino)-4-phenylbutane-1,2-diol and the reaction product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to provide (183 mg (0.887 mmol, yield 70%) of (4R,5R)-5-hydroxymethyl-4-phenylmethyloxazolidinone as crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31]CC7C=CC=CC=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH:42]1([CH2:45]Br)[CH2:44][CH2:43]1>>[CH:42]1([CH2:45][O:31][C:27]2[C:26]([O:39][CH3:40])=[C:25]3[C:30]([C:21]([N:17]4[CH2:16][C:15]5[CH:41]=[C:11]([C:8]6[CH:9]=[CH:10][C:4]7[N:3]=[C:2]([CH3:1])[NH:6][C:5]=7[CH:7]=6)[CH:12]=[CH:13][C:14]=5[O:20][CH2:19][CH2:18]4)=[N:22][CH:23]=[N:24]3)=[CH:29][CH:28]=2)[CH2:44][CH2:43]1
Reactant: COc1c(OCc2ccccc2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12
Reactant: BrCC1CC1
Product: COc1c(OCC2CC2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12

Procedure:
Synthesized according to the method of example 10 using 7-(2-methyl-1H-benzimidazol-6-yl)-4-{8-(methyloxy)-7-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) in step 1 and cyclopropylmethyl bromide in step 2. 1H NMR (400 MHz, d6-DMSO): 8.66 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.81 (m, 3H), 7.63 (d, 1H), 7.50 (d, 1H), 7.04 (d, 1H), 5.44 (s, 2H), 4.63 (br s, 3H) 4.53 (br s, 2H), 4.17 (d, 2H), 3.92 (s, 3H), 0.83 (m, 1H), 0.61 (m, 2H), 0.41 (m, 2H); MS (EI) for C30H29N5O3: 508 (MH+).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.Cl.[N:26]([O-])=O.[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[N:26][N:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cn2ccnc2)cc1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-n2nnc3ccc(Cn4ccnc4)cc32)cc1
Temperature: 0 °C
Yield: 49 %

Procedure:
A mixture of 1.6 parts of 4-(1H-imidazol-1-ylmethyl)-N2 -phenyl-1,2-benzenediamine, 20 parts of acetic acid and 1.08 parts of concentrated hydrochloric acid was cooled in an ice bath at 12°-16° C. A solution of 0.83 parts of sodium nitrite in 7 parts of water was added dropwise. Upon complete addition, the reaction mixture was allowed to reach room temperature while stirring. The reaction mixture was poured into alkaline ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel first using a mixture of trichloromethane and methanol, saturated with ammonia, (97.5:2.5 by volume) and then a mixture of ethyl acetate, methanol and methanol, saturated with ammonia (95:2.5:2.5 by volume) as eluents. The pure fractions were collected and the eluent was evaporated. The residue was taken up in a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 0.81 parts (49.0%) of 6-(1H-imidazol-1-ylmethyl)-1-phenyl-1H-benzotriazole; mp. 110.1° C. (compound 72).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C@@H:12]1[C:21]2[C:16](=[C:17]([Br:24])[CH:18]=[C:19]([CH2:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:26][C:27]1[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C@@H:12]1[C:21]2[C:16](=[C:17]([Br:24])[CH:18]=[C:19]([CH2:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CCc1cc(Br)c2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(Br)c2c(c1)[C@@H](NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCC2
Reaction time: 1.5 h
Yield: 106.1 %

Procedure:
Compound 3 (995 mg) is dissolved in 10 mL of anhydrous CH2Cl2 followed by the addition of 10 mL of trifluoroacetic acid (anhydrous). The solution stands for 90 min. then the volatiles are removed with a stream of nitrogen. The compound is desalted by extraction between ethyl acetate, 10 mL, and saturated aqueous sodium bicarbonate, 20 mL. The ethyl acetate phase is washed a second time with saturated sodium bicarbonate. The organic phase is then dried with MgSO4 (anhydrous), filtered, and evaporated of volatiles yielding 865 mg of 4 ([M+H]+=452.8).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccccc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester Example 283, Step 2) and phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C18H20O5 [M+Na]+: 339.3.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:12]=3[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:31]([NH:23][S:20]([C:18]2[CH:17]=[CH:16][C:13]3[CH2:14][CH2:15][N:9]([C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])[CH2:10][CH2:11][C:12]=3[CH:19]=2)(=[O:22])=[O:21])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCCC1)CC2
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-(1-piperidinylcarbonyl)-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-{[2,3,4,5-tetrahydro-3-(1-piperidinylcarbonyl)-1H-3-benzazepin-7-yl]sulfonyl}urea, m.p. 166°-167° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with 1-piperidine-carbonyl chloride in a manneranalogous to that described in Example 1.
Reaction SMILES: O1C=CC[CH:2]1C(O)=O.[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:19]([OH:21])=[O:20].CC(C)([O-])C.[K+].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>O1CCCC1>[CH3:2][C:10]1([C:19]([OH:21])=[O:20])[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9]1
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: O=C(O)C1CC=CO1
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2ccccc2O1

Procedure:
The title compound was prepared following the procedures described for Reference Example 5 substituting 2,3-dihydrofuran-2-carboxylic acid with chromane-2-carboxylic acid at Step A and potassium tert-butoxide in tetrahydrofuran with potassium hexamethyldisilazide (0.5 M in toluene) at Step B. 1H NMR (500 MHz, CD3OD): δ 7.07 (t, 1H), 7.03 (d, 1H), 6.82 (m, 2H), 2.75 (m, 2H), 2.40 (m, 1H), 1.80 (m, 1H), 1.60 (s, 3H).
Reaction SMILES: C(S(N1CCC(C2C3C(=C(C(N)=O)C=C([C:21]4[S:22][C:23]([CH2:26][NH:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH3:31])=[CH:24][CH:25]=4)C=3)NC=2)CC1)(=O)=O)C.C(C1SC([B:43]([OH:45])[OH:44])=CC=1)=O.C[C@@H](CC)CN.[BH3-]C#N.[Na+]>>[CH3:32][C@@H:29]([CH2:30][CH3:31])[CH2:28][NH:27][CH2:26][C:23]1[S:22][C:21]([B:43]([OH:45])[OH:44])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: CC[C@H](C)CN
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@H](C)CNCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(2S)-2-methylbutyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 37.6 mg of the title compound (39%).