Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([N:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[CH2:26]([C:30](O)([C:35]([OH:37])=O)[CH2:31][C:32]([OH:34])=O)[C:27]([OH:29])=O.[C:39]([O-])(=O)[CH2:40]CCCCCCCCCCCCCCCC.[Mg+2].C([O-])(=[O:78])CCCCCCCCCCCCCCCCC>>[CH2:12]=[CH:17][CH2:16][N:15]1[C@@H:18]2[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([OH:78])=[C:32]4[O:34][C@H:26]5[C:27]([CH2:39][CH2:40][C@:35]2([OH:37])[C@:30]5([C:31]=34)[CH2:13][CH2:14]1)=[O:29].[CH3:1][CH2:2][C:3]([N:5]([CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Agent: [Mg+2]
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5

Procedure:
Fentanyl citrate, croscarmellose sodium and silicified microcrystalline cellulose, and then magnesium stearate, were all added and admixed under the same conditions as those described in Examples 1 and 2 above. The mixture was compressed as described in Example 2.
Reaction SMILES: C1(C)C=CC=CC=1C(C1C=CC=CC=1C)CCCI.[C:20]1([CH3:38])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[CH:27][CH2:28][CH2:29][NH2:30]>>[C:20]1([CH3:38])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])[CH2:27][CH2:28][CH2:29][NH2:30]
Reactant: Cc1ccccc1C(=CCCN)c1ccccc1C
Agent: Cc1ccccc1C(CCCI)c1ccccc1C
Product: Cc1ccccc1C(CCCN)c1ccccc1C

Procedure:
Prepared via the 4,4-di-(2-tolyl)-1-butyliodide, 33a and isolated as an oil. 1H NMR (CDCl3) δ1.20 (s broad, 2H), 1.42-1.58 (m,2H), 1.87-2.03 (m,2H), 2.27 (s,6H), 2.70 (t,2H), 4.23 (t,1H), 7.05-7.16 (m,8H) 4,4-Di-(2-tolyl)-3-butenylamine, 30c. Prepared via the 4,4-di-(2-tolyl)-3-butenylodide 36a and isolated as an oil. 1H NMR (CDCl3) δ1.20 (s broad, 2H), 2.11 (s,3H), 2.18 (q,2H), 2.26 (s,3H), 2.77 (t,2H), 5.75 (t,1H), 7.02-7.18 (m,8H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=[N:17]O)[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-]>[Ni].C(O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1
Reactant: ON=C1CCN(c2cccc3c2OCCC3)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC1CCN(c2cccc3c2OCCC3)CC1
Reaction time: 5 h
Yield: 89.5 %

Procedure:
0.9 g of the product obtained in Step 2 is hydrogenated at room temperature and atmospheric pressure in the presence of 1 ml of Raney nickel and1 ml of concentrated NH4OH in 20 ml of ethanol. After 5 hours' contact, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is taken up in 100 ml of methylene chloride and extracted with 1N hydrochloric acid. The acid phase is rendered basic with concentrated sodium hydroxide solution and extracted with methylene chloride. After washing, drying and evaporation, 0.76 g of the expected product is isolated.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)Cl>[Br:17][C:7]1[N:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1cnc(CC)c(NC(CC)CC)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCc1nc(NC(CC)CC)c(CC)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A 500 mL dry round bottom flask equipped with a magnetic stir bar was charged with 3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine (10.0 g, 45.18 mmol) and CH2Cl2 (220 mL). After the mixture was cooled with an ice bath, N-bromosuccinimide (8.84 g, 49.7 mmol) was added at once. The mixture was stirred at 0° C. for 30 minutes then quenched with saturated aq. NaHCO3, diluted with H2O and extrated twice with CH2Cl2. The organics were combined, dried with NaSO4, filtered and concentrated to 13.96 g of a brown oil. The crude was purified by Biotage MPLC in two batches (120 g columns, 2.5% ethyl acetate in heptane.) Like fractions were combined to give 11.57 g (85%) of 5-bromo-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH:38]([NH2:41])([CH3:40])[CH3:39]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][CH:38]([CH3:40])[CH3:39])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: CC(C)N
Product: CC(C)Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.20 g, 0.35 mmol) and isopropylamine (2 mL) the title compound was obtained as a yellow solid (0.15 g, 0.25 mmol, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 14.28 (br. s., 1H), 8.35 (d, J=7.2 Hz, 1H), 7.84 (s, 1H) 7.67-7.51 (m, 2H), 7.47 (d, J=6.8 Hz, 1H), 7.33-7.07 (m, 3H), 5.90 (d, J=6.6 Hz, 1H), 4.08 (dq, J=13.3, 6.7 Hz, 1H), 3.88-3.73 (m, 4H), 3.71-3.52 (m, 4H), 1.27 (d, J=6.4 Hz, 6H). MS (ESI): 591 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:30]4[C:29]5[CH:28]=[C:27]([C:31]6[CH:32]=[N:33][C:34]7[C:39]([CH:40]=6)=[CH:38][CH:37]=[CH:36][CH:35]=7)[CH:26]=[CH:25][C:24]=5[N:23]=[CH:22][C:21]=4[C:20](=[O:41])[O:19][C:18]3=O)=[CH:13][C:12]=2[C:43]([F:46])([F:45])[F:44])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[CH3:47][NH2:48]>C1COCC1.C(Cl)Cl>[CH3:47][N:48]1[C:20](=[O:41])[C:21]2[CH:22]=[N:23][C:24]3[CH:25]=[CH:26][C:27]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:28][C:29]=3[C:30]=2[N:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:10][CH2:9]3)=[C:12]([C:43]([F:46])([F:44])[F:45])[CH:13]=2)[C:18]1=[O:19]
Reactant: CCC(=O)N1CCN(c2ccc(-n3c(=O)oc(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(=O)N1CCN(c2ccc(-n3c(=O)n(C)c(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a solution of compound 5.6 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)-1H-[1,3]oxazino[5,4-c]quinoline-2,4-dione (20 mg, 0.032 mmol, 1 equiv.) in THF/CH2Cl2 (5 mL, 1:1) at room temperature was added MeNH2 (5 mg, 0.16 mmol, 5 equiv.). The resulting solution was heated to 40° C. and stirred for 2 h. Upon concentration, the mixture was purified via preparative LC-MS (CH3CN:H2O) to furnish the desired compound 5.7 3-methyl-1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)pyrimido[5,4-c]quinoline-2,4(1H,3H)-dione (3 mg). LC-MS (M+H): 639.49
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]([Cl:28])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.B(OC)(OC)[O:30]C.Cl>CCCCCC.O1CCCC1>[Cl:28][C:9]1[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=[C:7]([OH:30])[CH:8]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2Cl)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
18.9 ml (30.30 mmol) of 1.6M n-BuLi solution in n-hexane are added dropwise at 0° C. to 4.50 g (12.10 mmol) of 5-bromo-3-chloro-2-(4-octyloxyphenyl)pyridine and 2.7 ml (24.20 mmol) of trimethyl borate in 70 ml of tetrahydrofuran, and the mixture is stirred at 0° C. for 0.5 hour. The mixture is subsequently acidified by means of dilute hydrochloric acid and partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is evaporated. The dry residue is dissolved in 100 ml of tetrahydrofuran and refluxed for 2 hours with 5 ml of 35% strength hydrogen peroxide. After the mixture has been cooled to 0° C., 6.3 g of Na2SO3 in 45 ml of water are added dropwise, and the mixture is stirred at room temperature for a quarter of an hour. The mixture is subsequently partitioned between ether and aqueous sodium chloride solution, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is evaporated to dryness. Chromatographic purification (silica gel, dichloromethane:ethyl acetate=4:1) gives 2.35 g of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)pyridine. ##STR18## m.p.: 128°-129.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[N:11]=3)[S:7][C:6]=2[CH:27]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:29]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][C:38]([NH:40][C:2]2[CH:3]=[CH:4][C:5]3[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)[N:11]=4)[S:7][C:6]=3[CH:27]=2)=[O:39])=[CH:29]1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccc(Br)cc4s3)n2)CC1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: CN1CCN(CCCNc2nccc(-c3cc4ccc(NC(=O)Cc5c[nH]c6ccccc56)cc4s3)n2)CC1
Temperature: 150 °C
Yield: 26.6 %

Procedure:
A microwave tube is charged with [4-(6-bromobenzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine (0.070 g, 0.16 mmol), 1.5 equivalent of 2-(1H-indol-3-yl)acetamide (0.041 g, 0.24 mmol), 4 mol % of tris(dibenzylideneacetone)dipalladium(0) (5.8 mg, 0.0063 mmol), 8 mol % of Xantphos (7.3 mg, 0.013 mmol), 1.5 equivalent of cesium carbonate (77 mg, 0.24 mmol) and acetonitrile (2 mL). The reaction is sealed and heated under microwave condition at 150° C. for 5 minutes, cooled down, filtered and then evaporated to furnish a red oil. This material is subjected to reverse phase purification, eluting with 20-95% CH3CN/0.01 M NH4HCO3 in water using a C18 Xterra column, to provide the title compound as a pale yellow solid (23 mg, 26% yield). ES+(m/z) 540 [M+H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1>O1CCCC1>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a room temperature solution of 3.27 g lithium aluminum hydride in 80 ml of dry tetrahydrofuran is added, dropwise, 10 g of product from Example 1 in 70 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 51/2 hours, quenched with a saturated sodium sulfate solution, filtered and the filtrate concentrated in vacuo. The residue is purified by column chromatography (silica gel:20% ethyl acetate/hexane) to give 9.0 g of desired product as colorless needles.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(C)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and (6-methyl-3-pyridinyl)boronic acid (46 mg, 0.337 mmol). The product was collected as a white solid (99 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (br. s., 1H) 8.96 (d, J=2.02 Hz, 1H) 8.67 (br. s., 1H) 8.40 (s, 1H) 8.20 (s, 1H) 8.17 (dd, J=8.08, 2.53 Hz, 1H) 7.89 (s, 1H) 7.39 (d, J=8.08 Hz, 1H) 5.91 (s, 1H) 5.18 (quin, J=6.57 Hz, 1H) 4.43 (br. s., 1H) 4.42 (br. s., 1H) 2.52-2.58 (m, 5H) 2.13 (s, 3H) 1.52-1.58 (m, 2H) 1.52 (s, 3H) 1.50 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=458.3 [M+H]+
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([NH2:16])[C:11]([NH2:15])=[CH:12][C:13]=3[Cl:14])[CH2:4]2)[CH2:2]1.[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N:32]=[C:33]=S)[CH:26]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([NH:32][C:33]2[NH:16][C:10]3[CH:9]=[C:8]([N:5]4[CH2:6][CH2:7][C:3]5([CH2:1][CH2:2]5)[CH2:4]4)[C:13]([Cl:14])=[CH:12][C:11]=3[N:15]=2)[CH:26]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1cc(Cl)c(N2CCC3(CC3)C2)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (130 μL, 0.9 mmol) followed by 4-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-benzene-1,2-diamine (80 mg) were added to (4-chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (example 1, step (c), 69 mg, 0.2 mmol) in DMF (3 mL). The reaction mixture was stirred at rt overnight, then concentrated and purified by chromatography to give the sub-title compound.
Reaction SMILES: [CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(C(C)C)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of ethyl 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (1.2 g) in methanol (5 ml) and 2N NaOH (5 ml) was heated for 4 hours under reflux. The reaction mixture was concentrated to dryness and then dissolved in water, followed by neutralization with 1N-HCl to give crystals. Recrystallization from DMF-50% EtOH afforded colorless prisms (0.8 g, 71%), m.p. 265-267° C. (decomp.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21][C:32]([C:27]3[NH:28][C:29]([CH2:30][CH3:31])=[C:25]([Cl:24])[N:26]=3)=[O:33])[C@H:17]([O:22][CH3:23])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1NC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(NC(C)=O)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Methyl cis(±)-2-(acetylamino)-5-(4-amino-3-methoxypiperidin-1-yl)benzoate obtained in Example (185d) (210 mg, 0.65 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (113 mg, 0.65 mmol) were dissolved in DMA (3 ml). WSC hydrochloride (500 mg, 2.6 mmol) and HOBt (88 mg, 0.65 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain 120 mg of the title compound as crystals.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.[CH3:25]O>>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:25])=[O:9])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A solution of 2.0 g (7.19 mmoles) of [2-(2-fluorobenzoyl)-4-chlorobenzoic acid], in 40 ml of methanol and 0.3 ml of sulfuric acid was refluxed for 10 hrs and then evaporated. The residue was partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried and evaporated. The resulting oil was dissolved in 20 ml of dichloromethane, filtered through 25 g of Florisil and eluted with dichloromethane. The solvent was evaporated and the oil was crystallized from ether and recrystallized from dichloromethane/ether/petrol to give white rods: mp 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH:25](O)[CH3:26])[CH:22]=[CH:23][CH:24]=3)[N:15]=2)=[CH:10][C:9]=1[C:28]([F:31])([F:30])[F:29].[NH2:32][C@@H:33]([CH3:41])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=3)[CH2:25][CH2:26][NH:32][C@@H:33]([CH3:41])[C:34]([OH:36])=[O:35])[N:15]=2)=[CH:10][C:9]=1[C:28]([F:31])([F:30])[F:29]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(C(C)O)c3)no2)cc1C(F)(F)F
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(CCN[C@@H](C)C(=O)O)c3)no2)cc1C(F)(F)F

Procedure:
The title compound was prepared following the protocol used for Example 91, Steps 2 and 3, but starting from (3-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (84 mg, 0.2 mmol) and (S)-tert-butyl 2-aminopropanoate (87 mg, 0.6 mmol). It was isolated as a white solid (133 mg, 96%). 1H NMR: (DMSO-d6, 400 MHz) δ 8.57 (s, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.07-8.03 (m, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.65-7.53 (m, 2H), 7.44-7.37 (m, 2H), 7.33 (td, J=4.0, 2.1 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 3.31 (q, J=7.2 Hz, 2H), 3.18-3.02 (m, 3H), 2.06 (s, 3H), 1.33 (d, J=7.0 Hz, 3H). LC/MS (Method B): 496 (M+H)+. HPLC (Method G) Rt 3.24 min (Purity: 99.1%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16]
Reactant: [H][H]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: COCCN1CC(c2ccccc2)NC1=O

Procedure:
Approximately 10.9 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 1 g. of 10% palladium on carbon in 100 ml. of ethanol is hydrogenated in a Parr Shaker apparatus at 30 psig of hydrogen for 45 minutes. The catalyst is filtered, washed with ethanol, and the filtrate is concentrated to give the title compound as a waxy white solid; m.p. 82°-83° C.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[NH:11][CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][NH2:20]>C(O)C>[NH2:19][N:20]1[C:1]([OH:8])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10](=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)[N:11]=[CH:12]1
Reactant: NN
Reactant: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCO
Product: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 0.1 mole of 2'-benzoyl-4'-chloroformanilide and 0.15 mole of hydrazine are stirred at room temperature in ethanol. Stirring is continued for 20 hours. The reaction mixture is chilled, and the precipitate filtered. The solid is washed and recrystallized from dimethylformamide to give 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Cl)ccc1S(C)(=O)=O
Reactant: Nc1ccn(CCCO)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCO)n2)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 30 mg, 0.21 mmol), 2,6-lutidine (34 μL, 0.29 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionyl chloride in methylene chloride (prepared in example 81, 0.096 M solution, 2 mL, 0.19 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×10 mL). The organic extracts were then combined and washed with a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (59 mg, 67%) as a white foam: [α]31589=−21.2° (c=0.17, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2109; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.19 (m, 2H, CH2), 1.35-1.81 (m, 8H, 4×CH2), 1.78-1.90 (m, 2H, CH2), 2.03-2.16 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.27-3.39 (m, 2H, OCH2), 3.82-3.94 (m, 1H, ArCH), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.56 (t, J=5.0 Hz, 1 H, OH), 6.40 (d, J=2.1 Hz, 1H, Ar), 7.41-7.49 (m, 2H, Ar), 7.54 (d, J=2.1 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.74 (s, 1H, NH).