Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.O=C1O[CH2:21][CH2:20][O:19]1>[I-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C.O1CCCC1>[OH:19][CH2:20][CH2:21][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: O=C1OCCO1
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCO)c(-n2cccc2)c1
Temperature: 140 °C
Yield: 69.3 %

Procedure:
The mixture of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (1.5 g), 2-oxo-1,3-dioxolane (0.61 g) and tetraethylammonium iodide (0.38 g) was heated at 140° C. for 3 hours. The resultant mixture was dissolved in the solution of ethyl acetate and tetrahydrofuran. The solution was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave the residue, which was purified by column chromatography on silica gel eluting with the solution of chloroform and ethyl acetate (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 4-(2-hydroxyethoxy)-3-(pyrrol-1-yl)benzoate (1.25 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[SH2:21].[Na]>CN(C)C=O>[CH:7]1[N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:18]2[C:5](=[C:4]([NH2:20])[NH:3][C:2]([N:19]=2)=[S:21])[N:6]=1
Reactant: S
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
The starting material, the 2-thioadenosine of the formula (IV), used in the above Process 2 can be obtained in high yield from 2-chloroadenosine of the formula (II) by the procedure disclosed in Japanese Patent Application OPI No. 52,795/1973. That is, 2-chloroadenosine is reacted with sodium hydrogen sulfide in a solvent such as dimethylformamide at a temperature of about 50°C to 100°C to obtain the desired 2-thioadenosine of the formula (IV) in about 100% yield. The preparation of the starting material of the formula (IV) will be hereinafter described in greater detail in Reference Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br.O>CN(C)C=O>[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:34]=[CH:33][C:15]2[N:16]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COc1ccc(-n2c(-c3ccccc3)nc3cc(NS(=O)(=O)c4ccc(Cl)cc4)ccc32)cc1
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccc(OC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
75 mg of 4-chloro-N-[1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-5-yl]benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 6 mg of sodium hydride and stirred for 30 minutes at 20° C. 44 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22](Cl)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:35][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccc(Cl)cc1

Procedure:
The title compound was prepared as a gum from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate and 4-chlorothiophenol by a procedure similar to that described in Example 23.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25](I)=[C:24]([CH:27]2[CH2:30][CH:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25]([CH:36]2[CH2:38][CH2:37]2)=[C:24]([CH:27]2[CH2:30][CH:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2I)C1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
tert-Butyl 6-benzyloxy-3-{5-[3-(2,2-dimethylpropyl)cyclobutyl]-4-iodoisoxazole-3-yl}hexanoate (4.20 g), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.34 g), tripotassium phosphate (5.92 g), DMF (90 mL) and water (10 mL) were mixed. The mixture was degassed by bubbling argon gas. To the mixture was added PdCl2(PPh3)2 (734 mg). The mixture was stirred at 80° C. for 1 hr. To the reaction mixture was added ethyl acetate, and then the mixture was filtered. The aqueous layer was removed, and the organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/25) to give the title compound (980 mg). A mixture of the title compound and impurities thereof (1.24 g) was also obtained.
Reaction SMILES: C([O:8][C:9]1(O)[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][CH:10]1[C:22]1[N:23]([CH3:36])[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:25](Cl)[N:26]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:24]2[N:23]([CH3:36])[C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:26][CH:25]=2)=[CH:34][CH:33]=1
Reactant: Cn1c(C2N=C3N(CCOC3(C)C)C(=O)C2(O)OCc2ccccc2)nc(Cl)c1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1c(Cc2ccc(F)cc2)cnc1-c1nc2n(c(=O)c1O)CCOC2(C)C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
To a solution of 3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-1-methyl-1H-imidazol-2-yl)-3-hydroxy-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (0.02 g, 0.039 mmol, 1.0 equiv) in EtOH (1 mL) was added ammonium formate (0.04 g, 0.634 mmol, 16 equiv) and 10% Pd/C (0.04 g, 0.376 mmol, 9.6 equiv). After stirring 4 h, LCMS analysis indicated complete conversion to product. The reaction was then filtered through celite and concentrated in vacuo. The crude product was purified by silica gel chromatography (7% MeOH/CH2Cl2) to provide the title compound (0.008 g, 53% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.19 (m, 2H), 6.97-7.06 (m, J=8.62, 6.48, 2.27 Hz, 2H), 6.90 (s, 1H), 3.99-4.09 (m, 4H), 3.97 (s, 2H), 3.95 (s, 3H), 1.57 (s, 6H); LCMS (ES+, (M+H)+) m/z 385.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:38](COCC[Si](C)(C)C)[C:37]([O:47][C@H:48]3[CH2:57][O:56][C@H:55]4[C@@H:50]([O:51]C(C5C=CC=CC=5)[O:53][CH2:54]4)[CH2:49]3)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([O:27]COCC[Si](C)(C)C)[CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(O)=O.S([O-])(O)(=O)=O.[K+].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:38][C:37]([O:47][C@@H:48]3[CH2:49][C@H:50]([OH:51])[C@@H:55]([CH2:54][OH:53])[O:56][CH2:57]3)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[O:21])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCO[C@@H]1CCN(C(=O)c2ccc(-c3ccc(-c4nc5nc(O[C@H]6CO[C@@H]7COC(c8ccccc8)O[C@H]7C6)n(COCC[Si](C)(C)C)c5cc4Cl)cc3)cc2)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Product: O=C(c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4′-(6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)((R)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyrrolidin-1-yl)methanone (181 mg, 0.198 mmol) in formic acid (1 ml, 26.1 mmol) at 0° C., was added saturated potassium hydrogen sulfate (0.2 ml, 0.198 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was then cooled down to 0° C. and basified to pH 11 with 2.5N NaOH. The mixture was stirred at room temperature for 30 minutes, then the layers were separated. The aqueous layer was extracted with EtOAc; and the combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The purification of the resulting residue by HPLC eluting with 10-100% MeCN:H2O 0.1% formic acid afforded the title compound LC-MS: calculated for C29H29ClN4O6 564.18 observed m/e: 565.09 (M+H)+ (Rt: 1.72/4 min).
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH3:6])C.[OH-].[K+]>C(O)C>[CH3:13][C:5]([CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)([CH3:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(C)(C)C1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.795 g of 2-methyl-2-(tetrahydro-pyran-4-yl)-propionic acid ethyl ester in 3 ml of ethanol is admixed with 3 ml of a 40% aqueous potassium hydroxide solution and then heated to reflux. After 4 hours, the reaction mixture is cooled to room temperature and the ethanol removed in vacuo. The remaining aqueous solution is acidified (pH 2-3) with 4M HCl and then extracted with tert-butyl methyl ether (2×). The combined organic layers are washed with water and brine, dried over sodium sulphate and concentrated by evaporation to provide the crude title compound as a yellow solid. Rf=0.10 (1:3 EtOAc-heptane).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[CH:10](=[O:13])[CH:11]=[CH2:12].[O-]CCCC.[Na+]>>[CH2:1]([P:3]([CH2:12][CH2:11][CH:10]=[O:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: C=CC=O
Reactant: CCCCOP([O-])CC
Agent: CCCC[O-]
Agent: [Na+]
Product: CCCCOP(=O)(CC)CCC=O
Yield: 88.9 %

Procedure:
A 1 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel was initially charged with 447 g (3 mol) of butyl ethylphosphonite (produced as in Example 3) and 168 g (3 mol) of 2-propenal. While stirring, 15 ml of sodium butoxide (30% in butanol) are added dropwise at such a rate that a reaction temperature of max. 120° C. becomes established. The crude product thus obtained is distilled in vacuo to obtain 550 g (89% of theory) of butyl ethyl(2-formylethyl)phosphinate as colorless liquid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:10](=[O:20])[N:11]([CH2:16][C:17]([OH:19])=[O:18])[C:12]([CH3:15])=[CH:13][N:14]=2)=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17]([OH:19])=[O:18])[C:12]([CH3:15])=[CH:13][N:14]=1
Reactant: COc1ccc(CNc2ncc(C)n(CC(=O)O)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N)c(=O)n1CC(=O)O

Procedure:
The pyrazinone 18-6 (900 mg) was heated at reflux in trifluoroacetic acid (20 mL) for 7 h. The volatiles were removed in vacuo and the residue was azeotroped with CH2Cl2, then EtOAc then MeOH. MeOH was added to the residue and the solution filtered to remove impurities. Removal of the methanol then afforded the title compound 18-7 which was used as such:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:57][N:58]([CH3:67])[C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.COCCOC>[CH3:57][N:58]([CH3:67])[C:59]([N:61]1[CH2:62][CH2:63][N:64]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=4)[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[CH2:65][CH2:66]1)=[O:60]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(=O)N(C)C)CC4)cc3)CC2)c(C)c1
Yield: 20.1 %

Procedure:
To a mixture of [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (270 mg) described in Preparation Example 113, palladium acetate (8 mg), 2-(dicyclohexylphosphino)biphenyl (22 mg), tripotassium phosphate (190 mg) and piperazine-1-carboxylic acid dimethylamide (111 mg) was added 1,2-dimethoxyethane (5 mL), and the mixture was stirred with heating under reflux for 7 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by NH coated silica gel column chromatography (ethyl acetate:hexane) to give the title compound (58 mg).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:7]2[C:6]([CH3:32])=[CH:5][N:4]=1.[CH3:33][N:34]1[C:38]([CH:39]=O)=[N:37][C:36]([N:41]2[CH2:45][CH2:44][CH2:43][CH:42]2[CH3:46])=[N:35]1>>[CH3:2][C:3]1[N:8]2[N:9]=[C:10](/[CH:12]=[CH:39]/[C:38]3[N:34]([CH3:33])[N:35]=[C:36]([N:41]4[CH2:45][CH2:44][CH2:43][CH:42]4[CH3:46])[N:37]=3)[N:11]=[C:7]2[C:6]([CH3:32])=[CH:5][N:4]=1
Reactant: CC1CCCN1c1nc(C=O)n(C)n1
Reactant: Cc1cnc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Product: Cc1cnc(C)n2nc(/C=C/c3nc(N4CCCC4C)nn3C)nc12
Yield: 73.6 %

Procedure:
Was prepared in the same manner as described in Example 49e) using ((5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (350 mg, 763 μmol, Eq: 1.00) and 1-methyl-3-(2-methylpyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (148 mg, 763 μmol, Eq: 1.00) affording 5,8-dimethyl-2-{(E)-2-[2-methyl-5-(2-methyl-pyrrolidin-1-yl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-c]pyrimidine (190 mg, 73.6%) as a bright yellow solid. MS: m/z=339.5 (M+H+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH2:8][N:7]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:5])[CH3:2].B.[O:29]1CCCC1>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([OH:29])[CH2:8][N:7]1[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@@H]1CC(c2ccc(OC)cc2)=CCN1c1ccc(OC)cc1
Agent: B
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1c1ccc(OC)cc1
Temperature: 40 °C

Procedure:
To a stirred solution of 19.5 g of (S)-1,4-bis-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid ethyl ester in 400 ml of tetrahydrofuran are added 56 ml of a solution of borane-tetrahydrofuran (1M) at room temperature. The reaction mixture is heated to 40° C. for 2-6 hours, cooled to room temperature, and quenched by the addition of 50 ml of 2N sodium hydroxide solution and 100 ml of 30% hydrogen peroxide solution. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow solid. Rf=0.33 (EtOAc-heptane 1:1); Rt=3.58.
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][C:19]1[S:20][CH:21]=[C:22]([CH:24]=O)[N:23]=1>COCCOC.C(OCC)(=O)C>[CH3:18][C:19]1[S:20][CH:21]=[C:22](/[CH:24]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:23]=1
Reactant: Cc1nc(C=O)cs1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nc(/C=C/c2ccccc2)cs1
Temperature: 0 °C
Yield: 65.6 %

Procedure:
Sodium hydride (120 mg of a 60% suspension in mineral oil, 3.0 mmol) was slurried in DME (6 mL) and cooled to 0° C. Diethyl benzylphosphonate (1.1 g, 5.0 mmol) was added dropwise and after 15 minutes, 2-methyl-1,3-thiazole-4-carbaldehyde (320 mg, 2.5 mmol) in DME (5 mL) was added dropwise to the reaction mixture. After 3 h at 0° C. the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous NH4Cl (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 90:10 hexane:ethyl acetate to afford 2-methyl-4-[(E)-2-phenylethenyl]-1,3-thiazole (330 mg, 65% yield) as an oil. 1H NMR (CDCl3, 300 MHz) δ 7–7.5 (m, 8H), 2.7 (s, 3H). MS (ESI) 202.1 (M++H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[I-:18].[Na+].C(OC)(C)(C)C>CC(C)=O>[I:18][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
1.74 g of 4-Chloromethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole and 3 g of sodium iodide in 150 ml of acetone are heated under reflux for 2 hours. After the reaction mixture has been cooled, 300 ml of methyl tert-butyl ether are added, the mixture is washed three times with saturated Na2S2O3 solution and dried over MgSO4 and the solvents are then removed under reduced pressure. This gives 2.64 g of 4-iodomethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole as a yellowish solid. C14H16INO (341.19), MS(ESI): 342 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:27]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35])([CH3:30])([CH3:29])[CH3:28]>CO>[C:27]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Solvent: CO
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NCC(C)(C)C(=O)OC(C)(C)C)nc(C#N)c3c2)cc1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (91 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (90 mg) in MeOH (3 mL) was heated at 100° C. in an oil bath for 48 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (84 mg). LC MS ESI+: 492 (M+1)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC(C(O)=O)CC1.C([O:38][C:39](=[O:50])[CH2:40][CH2:41][C@H:42]([NH:46]C(O)=O)[C:43](O)=[O:44])(C)(C)C>>[NH2:46][C@H:42]([C:43](=[O:44])[NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)=[CH:19][CH:20]=1)[CH2:41][CH2:40][C:39]([OH:50])=[O:38]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)O)C(=O)O
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: O=C(O)C1CCNCC1
Product: N[C@@H](CCC(=O)O)C(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
(S)-4-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric acid was prepared as described for piperidine-4-carboxylic acid [6-(2-phenyl-chroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S)-2-carboxyaminopentanedioic acid 5-tert-butyl ester.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([N:18]([CH2:25][CH2:26][CH3:27])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12]3)C=CC=CC=1>C(O)C.[Pd]>[CH2:25]([N:18]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:26][CH3:27]
Reactant: CCCN(c1ccncc1)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reaction time: 48 h
Yield: 98.1 %

Procedure:
To 0.3 g of 10% Pd/C in 10 ml of absolute ethanol was added 5-phenylmethoxy-1-(propyl-4-pyridinylamino)-1H-indole (3.0 g) in 240 ml of ethanol and this was hydrogenated on a Parr apparatus for 48 hours at 50° C. and 50 psig H2. The reaction mixture was then filtered and the filtrate concentrated to yield an oil (2.2 g), which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid (1.8 g) which was recrystallized from methanol/ether (1:1) to yield a solid 1.6 g, m.p. 214°-216° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH2:16].C1(C)C=CC=CC=1>C(O)C>[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH:16][C:11]([NH:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[S:12]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 49%).