Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=3)[C:14]([NH:16][C:17]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]3)=[O:15])[CH:9]=2)[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.[CH3:36]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:3]2[O:4][C:5]3=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=4)[C:14]([NH:16][C:17]4([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19]4)=[O:15])[CH:9]=[C:10]3[C:2]=2[CH3:36])=[CH:34][CH:33]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: O=C(NC1(c2ccccc2)CC1)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Pd(Ph3P)4 (16 mg, 0.014 mmol) was added to a stirring solution of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (75 mg, 0.14 mmol), trimethylboroxine (40 μL, 0.28 mmol), and Na2CO3 (45 mg, 0.43 mmol) in DMF (1.3 mL) and Water (0.13 mL) at room temperature. It was subjected to microwave irradiation: 180° C. for 30 min. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (61 mg, 0.132 mmol, 93% yield) consistent by LCMS. LC-MS retention time: 1.81 min; m/z (MH+): 463. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: COC([N:5]1[CH2:10][CH:9]([CH2:11][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:13][CH3:14])[C:8](=[O:24])N(C)C1C(C)(C)C)=O.Cl.[O:31]1CCOCC1>>[NH2:5][CH2:10][C@@H:9]([CH2:11][C@H:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[CH2:13][CH3:14])[C:8]([OH:24])=[O:31]
Reactant: C1COCCO1
Reactant: CCC(Cc1ccc(F)cc1F)CC1CN(C(=O)OC)C(C(C)(C)C)N(C)C1=O
Agent: Cl
Product: CC[C@@H](Cc1ccc(F)cc1F)C[C@H](CN)C(=O)O
Temperature: 110 °C
Yield: 24 %

Procedure:
A flask was charged with 0.5 g (1.2 mmol) of 2-tert-butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester, 20 mL dioxane, and 20 mL of conc. HCl solution. The mixture was stirred and heated at 110° C. for 4 days. The solvents were removed under reduced pressure. The residue was taken up in 20 mL of water and 4 drops of conc. HCl solution. The aqueous layer was washed with dichloromethane. The aqueous layer was collected and the water was removed under reduced pressure. The residue was treated with 2 mL of triethylamine, and the excess triethylamine was removed under reduced pressure. The remaining solid was purified by column chromatography (1:8:27 NH4OH, MeOH, dichloromethane eluent). The resulting white solid was washed with acetonitrile and dried under vacuum. This gave 80 mg (24% yield) of the titled compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
4 g (20 mmol) of ortho-bromonitrobenzene, 842 mg (1.2 mmol) of bis(triphenyl-phosphine)palladium(II) chloride and 230 mg (1.2 mmol) of copper(I) iodide were, under argon, initially charged in 40 ml of triethylamine. At room temperature, 2.95 g (30 mmol) of trimethylsilylacetylene were then added dropwise over a period of 10 min, and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into 50 ml of water and extracted three times with in each case 50 ml of diethyl ether, and the extracts were dried over sodium sulphate and concentrated. Column-chromatographic purification on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 3:1) gave 4.2 g (96% of theory) of trimethyl-(2-nitrophenyl-ethynyl)silane [log P (pH 2.3)=4.12].
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=O.BrBr.[NH2:22][C:23]([NH2:25])=[S:24].C(=O)([O-])O.[Na+]>C(O)C.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10]1[S:24][C:23]([NH2:25])=[N:22][C:11]=12
Reactant: CCCC(CCc1cccc2c1CCCC2=O)OC
Reactant: NC(N)=S
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCC(CCc1cccc2c1CCc1sc(N)nc1-2)OC
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a 10% methanol-chloroform (60 mL) solution of 5-(3-methyloxyhexyl)tetralone (6) (9.0 g) was added bromine (5.5 g), and the reaction mixture was stirred for 1 h. After the solvent was evaoprated, the residue was dissolved in ethanol (60 mL), and to the residue was added thiourea (2.65 g). After the mixture was heated at reflux for 7 h, the reaction solvent was evported. To the residue was added a saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to obtain the compoumd (7) 4.6 g.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH:17]([CH3:19])[CH3:18])[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[CH:17]([N:16]1[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=[C:12]1[CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:19])[CH3:18]
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2ccccc2n1C(C)C
Product: CC(C)n1c(CCC#Cc2ccccn2)nc2ccccc21
Yield: 41.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (81 mg, 0.39 mmol) and 2-(but-3-ynyl)-1-isopropyl-1H-benzo[d]imidazole (84 mg, 0.39 mmol). The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH: from 100/0 to 96/4 as eluent) to afford 47 mg of 1-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a light brown oil (Yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].O.Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reaction time: 10 h

Procedure:
To a solution of 38 mg (73 μmol) of ethyl 2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate (Example 49) in 0.75 mL of MeOH/THF/H2O (2/2/1) was added a 2M solution of lithium hydroxide in water (70 μl, 141 μmol) at 25° C. and the mixture was stirred for 10 h. The reaction was acidified (1N aq. HCl) and extracted with DCM (2×). The combined organic layers were successively washed with 10% aq. citric acid solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by reversed phase HPLC (10 to 90% AcCN/H2O with 0.1% TFA in 45 min) provided the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18][CH3:19])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]1([CH3:35])[CH3:34])(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=[O:44])C=1>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18]([CH3:19])=[O:44])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]1([CH3:35])[CH3:34])(=[O:3])[NH2:2]
Reactant: CSc1nnc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)o1

Procedure:
A solution of (R)-tert-butyl 4-((3-carbamoyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (306 mg, 0.610 mmol) and mCPBA (265 mg, 1.182 mmol) in chloroform (6 mL) was stirred at room temperature for 2 h. Additional mCPBA (78 mg) was added. After one more hour at room temperature, the staring material was consumed. The crude solution was taken to the next reaction without purification. MS (ES+) m/z: 518.3 (M+H).
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[N:14]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:21]>O>[ClH:21].[F:2][C:3]([F:12])([F:13])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][NH2:14]
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccccc1OC(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of hydrochloric acid (37%, 1.6 L) at 0° C. is added 2-trifluoromethoxy-phenylamine (200 g, 113 mmol) followed by water (160 mL) and additional hydrochloric acid (160 mL). The mixture is warmed to room temperature, is stirred for 20 minutes, and is cooled to −5° C. A solution of sodium nitrite (82 g, 1.19 mmol) in water (400 mL) is added dropwise keeping the internal temperature below 0° C. The mixture is cooled to −5° C. and a solution of tin (II) chloride dihydrate (1020 g, 4520 mmol) in of HCl (37%, 3.2 L) is added dropwise keeping the internal temperature below 0° C. The mixture is warmed to room temperature, is stirred for 3 h, filtered, and washed with 6 N HCl (3 L) to obtain a yellow solid that is dried under vacuum overnight The title compound (115.8 g, 54%) is obtained pink-brown solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][S:12][CH:13]1[N:16]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:31])[CH:14]1[CH:32]([O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])[CH3:33].[C:48](Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50]>O1CCCC1.C1(C)C=CC=CC=1.Cl.C(Cl)Cl>[CH3:50][C:49]([CH3:52])([CH3:51])[C:48](=[O:53])[CH:17]([N:16]1[CH:13]([S:12][CH3:11])[CH:14]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH3:33])[C:15]1=[O:31])[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.1 ml of 1 M lithium bis(trimethylsilyl)-amide are added at -70° C. with stirring in the course of 5 minutes to a mixture of 275 mg (0.515 mmol) of p-nitrobenzyl 2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-acetate and 67 μl (0.55 mmol) of pivaloyl chloride in 6.7 ml of dry tetrahydrofuran and the reaction mixture is stirred at -70° C. during the course of a further 30 minutes and then diluted with 40 ml of toluene and with 30 ml of 2 N HCl, then washed twice with 40 ml each of NaCl solution. The organic phase is dried over MgSO4 and filtered, and the solvent is removed in vacuo. The residue is chromatographed on 10 g of silica gel using toluene/ethyl acetate (9:1), 268 mg of a white non-crystalline solid being obtained. IR spectrum in CH2Cl2 : 2930, 2850, 1775, 1760, 1720, 1610, 1535, 1350 cm-1 .
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:8][NH:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[NH:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[C:6]([OH:42])=[O:5])=[O:31])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCCNc2nc3ccccc3[nH]2)cc1)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(OCCCNc2nc3ccccc3[nH]2)cc1

Procedure:
A CH2Cl2 solution (20 mL) of 36-7 (580 mg, 0.97 mmol) and TFA (5 mL) was stirred under ambient conditions for 2 h and at 50° C. for 2 h. Concentration and flash chromatography (silica, 9:0.5:0.5 EtOH/H2O/NH4OH) gave 36-8 as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: O=C1CCc2cccc(O)c2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1CCc2c(C(=O)CCl)ccc(O)c2N1
Reaction time: 15 h
Yield: 37.7 %

Procedure:
13 g of 8-hydroxy-3,4-dihydrocarbostyril (VII) and 20 g of chloroacetyl chloride were dissolved in 100 ml of nitrobenzene, and 40 g of aluminum chloride was added slowly to the mixture followed by stirring for 15 hours at a temperature of 70° to 75°C. The mixture was then steam-distilled to remove nitrobenzene. After allowing the mixture to cool, the precipitated crystals were filtered, washed with hot water and recrystallized from methanol to give 7.2 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril (IV) as light yellow crystals having a melting point of 189° to 190°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C(N(CC)CC)C.O>FC(F)(F)C(O)=O>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:28]3[O:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:13][CH2:12]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2CCN(c3nc4ccccc4o3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
2-(4-tert-Butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 306 (500 mg, 1.36 mmol) was dissolved in trifluoroacetic acid (10 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and added methylene chloride (1 ml) and triethylamine (1 ml). The solution was stirred at room temperature for 5 minutes, and then concentrated under reduced pressure. The residue was dissolved in methylene chloride. To the solution, 2-chlorobenzoxazole (0.19 ml, 1.63 mmol) and triethylamine (0.23 ml, 1.63 mmol) were added followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford 2-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]benzoxazole (325 mg, yield 62%) as a white powder.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:4]=1
Reactant: CO
Reactant: Clc1cc(-n2cccn2)ncn1
Agent: [Na]
Product: COc1cc(-n2cccn2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 3 ml of anhydrous methanol, 23 mg of sodium metal was dissolved, and to the resulting solution, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine in 2 ml of anhydrous methanol was added dropwise with stirring at room temperature in a stream of nitrogen overnight. The solvent was distilled off under reduced pressure, and the residue was extracted with 20 ml of methylene chloride. The organic layer was washed with 5 ml of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled away, and a residue was purified by a silica gel column chromatography using chloroform to give an amorphous product. The product was recrystallized from n-hexane to provide 132 mg of the plate crystal 6-methoxy-4-(1-pyrazolyl)pyrimidine having a melting point of 108.5°-109° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[NH2:22][C@@H:23]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=1)[C@H:24]([OH:36])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH3:35])[CH:29]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:10]=[C:11]([C:14]([NH:22][C@@H:23]([CH2:37][C:38]3[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=3)[C@H:24]([OH:36])[CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH3:35])[CH:29]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1ccc2c(-c3ncco3)cc(C(=O)O)cc21
Solvent: ClCCl
Product: CCCCn1ccc2c(-c3ncco3)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.3 %

Procedure:
To a mixture of 1-butyl-4-(1,3-oxazol-2-yl)-1H-indole-6-carboxylic acid (0.2 g) in methylene chloride (20 mL) was added 1,1-carbonyldiimidazole (0.114 g). The mixture was stirred at room temperature for 1 h at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.265 g) dissolved in methylene chloride (10 mL) was added. The mixture was stirred at room temperature for 18 h then poured into methylene chloride (50 mL), washed with water followed by brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 65% methylene chloride, 30% hexanes, and 5% methanol as eluent to give 0.0985 g of the title compound: MS (ESI+) for C35H38F2N4O3 m/z 601.99 (M+H)+.
Reaction SMILES: ICCC[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.ClC1C=CC=[C:19]2C=1[CH:16]=[C:17](C(OCC)=O)[NH:18]2.N1C2C(=CC=CC=2)[CH:30]=[C:29]1C(OC)=O>>[CH3:19][N:18]1[C:10]2[C:9](=[CH:29][CH:30]=[C:12]([C:7]([O:6][CH3:5])=[O:8])[CH:11]=2)[CH:16]=[CH:17]1
Reactant: ICCCCOC1CCCCO1
Reactant: CCOC(=O)c1cc2c(Cl)cccc2[nH]1
Reactant: COC(=O)c1cc2ccccc2[nH]1
Product: COC(=O)c1ccc2ccn(C)c2c1

Procedure:
The title compound was prepared in a manner similar to Reference Example 5 (23) except that 2-(4-iodobutoxy)tetrahydropyran and ethyl 4-chloro-2-indolecarboxylate was used in place of 2-(2-iodoethoxy)tetrahydropyran and methyl 2-indolecarboxylate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:14]=[CH:13][NH:12][CH:11]=2)=O)=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:15][C:4]1[N:3]=[C:2]2[NH:17][N:18]=[C:8]([C:10]3[CH:14]=[CH:13][NH:12][CH:11]=3)[C:7]2=[CH:6][CH:5]=1
Reactant: O=C(c1cc[nH]c1)c1ccc(Cl)nc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(-c3cc[nH]c3)n[nH]c2n1
Temperature: 90 °C

Procedure:
A mixture of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-3-yl)-methanone (300 mg) and hydrazine hydrate (0.2 mL) in ethanol (10 mL) was heated at 90° C. for 20 hours. The reaction was concentrated to 6 mL, diluted with water (2 mL) and cooled. The precipitate was collected and dried to give 160 mg of the titled compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C[O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=1>C(OCC)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH2:16][C:15]([OH:14])=[O:25])[CH:22]=[CH:21][C:20]=1[O:23][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1
Reactant: C=CCOc1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1
Yield: 49.6 %

Procedure:
The noted compound was prepared in accordance with the procedure described in section (f) from 4-allyloxybenzyl chloride and methyl-3-chloro-4-hydroxy-phenylacetate in 49.6% yield, m.p. 106°-107° C. (ethyl acetate).
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[NH:3][CH:2]=1.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[ClH:13].[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:10]([CH:8]2[CH2:7][CH2:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:9]2)=[O:12])=[CH:16][CH:15]=1
Reactant: NCCCOc1ccc(Cl)cc1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Product: Cl
Product: O=C(NCCCOc1ccc(Cl)cc1)C1CCc2[nH]cnc2C1

Procedure:
By a similar procedure as described in Example 65, the title compound was prepared from 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid and 3-(4-chlorophenoxy)propylamine.