Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COCCOC.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=O)[C:23]([N:25]2[CH2:30][CH2:29][N:28]([N:31]=O)[CH2:27][CH2:26]2)=O)=[CH:14]1>O>[NH2:31][N:28]1[CH2:29][CH2:30][N:25]([CH2:23][CH2:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][CH:14]=2)[CH2:26][CH2:27]1
Reactant: O=NN1CCN(C(=O)C(=O)c2c[nH]c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: -5 °C

Procedure:
To a stirred mixture of 9.0 g of lithium aluminum hydride in 400 ml. of 1,2-dimethoxyethane is added 10.52 g (0.037 mol) of 1-(indol-3-ylglyoxyloyl)-4-nitrosopiperazine slowly to maintain reaction temperature below 35° C. After all the material is added, the mixture is refluxed for 14-16 hours. The reaction mixture is cooled to -5° C. and a solution of 50 ml. of water and 50 ml. of 1,2-dimethoxyethane is slowly added while maintaining the temperature below 15° C. Another 50 ml. of water is added, and the mixture is then filtered. The solvent is removed from the filtrate and the residual solid is recrystallized from benzene, producing the pure crystals of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole, m.p. 115°-117° C. Analysis: Calculated for C14H20N4 :68.82% C; 8.25% H; 22.93% N Found:68.70% C; 8.17% H; 22.55% N.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.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:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 78 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and Cul (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (R)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 18mg, 20%).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>CN(C=O)C>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:8][CH:9]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCC(=O)OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Under ice-cooling condition, to 25 ml of DMF solution containing 5.70 g of Z-Tyr-OCH3 was added 692 mg of sodium hydride (containing 60%) and the mixture was stirred for 30 minutes, then 3.96 g of benzyl bromoacetate was added thereto and the whole mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated sodium chloride aqueous solution twice, respectively, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was added to a silica gel column and eluted with petroleum ether-chloroform (1:4) to obtain 6.00 g (yield: 72.6%) of the above-mentioned objective product.
Reaction SMILES: [C:1]([CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].[C:24]1([N:30]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32](=O)[C:31]2=[O:41])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[O:3]=[C:1]([CH3:4])/[CH:2]=[C:32]1/[C:31](=[O:41])[N:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:33]/1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C(=O)N(c2ccccc2)C1c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)/C=C1/C(=O)N(c2ccccc2)C1c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.67 g of acetylmethylene triphenylphosphorane in 70 ml of benzene was added at room temperature under a nitrogen atmosphere a solution of 0.50 g of 1,4-diphenyl-2,3-azetidinedione in 30 ml of benzene, and the mixture was stirred overnight. After completion of the reaction, the benzene was evaporated, and the residue was applied to silica gel column chromatography (eluent; methylene chloride). The desired fractions were combined, the solvent was evaporated, and the residue was recrystallized from ethanol to give the title compound as pale yellow needles. Yield 0.32 g, m.p. 157.5°-158.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])([OH:3])=[O:2].[N+:18]([O-])([OH:20])=[O:19]>>[C:1]([C:4]1[CH:9]=[C:8]([N+:18]([O-:20])=[O:19])[CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C(=O)O)c1OC1CCOC1=O
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1OC1CCOC1=O
Temperature: 0 °C

Procedure:
24.4 g. of α-[(2-Carboxy-6-methylphenyl)oxy]-γ-butyrolactone was added to 120 ml. of fuming nitric acid at a temperature not higher than -40° C. The reaction solution was poured into ice water, and the precipitating crystals were collected by filtration, washed with water and dried. The crystals were recrystallized from methanol. By the above procedure there was obtained α-[(2-carboxy-6-methyl-4-nitrophenyl)oxy]-γ-butyrolactone as pale yellow prisms, m.p. 210° C.(decomp.). Yield 20.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C([N:53](CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]#[N:53])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C#N)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A suspension of 500 mg 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b), 111.2 mg ammonium chloride and 0.7 ml triethylamine in 5 ml tetrahydrofuran are cooled to −10° C. and 1.21 ml of a T3P® solution (50% in ethyl acetate) is added dropwise. The reaction mixture is warmed to room temperature and stirred for 8 hours. The resulting suspension is stirred at 70° C. for 2 days. During this time, the addition of 111.2 mg ammonium chloride, 0.7 ml triethylamine and 1.21 ml of a T3P® solution (50% in ethyl acetate) is repeated twice. The reaction mixture is quenched by addition of 5 ml of water and extracted with 50 ml ethyl acetate (3×). The combined organic layers are washed with brine and dried with sodium sulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless foam. Rf=0.12 (EtOAc-heptane 1:2); Rt=5.42.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1Cl
Product: COC(=O)c1nc(C)sc1-c1ccccc1Cl

Procedure:
prepared by reaction of 3-chloro-3-(2-chloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=268.0.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=[CH:11][CH:10]=1>C1C=CC=CC=1.CO>[CH3:1][O:2][C:3]([NH:5][N:6]=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]1=[CH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=1)=[O:4]
Reactant: COc1ccc(C=C2CCCCC2=O)cc1
Reactant: COC(=O)NN
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)NN=C1CCCCC1=Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 22.68 g (0.252 moles) of N-methoxycarbonyl hydrazine in 100 ml of benzene a solution of 50.0 g (0.23 moles) of 2-(p-methoxyphenylmethylene)-cyclohexan-1-one in 300 ml of anhydrous methanol is added, under stirring. The reaction mixture is boiled for one hour, clarified with activated carbon, filtered and the filtrate is cooled. 63.05 g of the desired compound are obtained. Yield: 94.65%.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][C:12](=[CH:15]OCC)[CH:13]=O>>[CH3:15][C:12]1[CH:11]=[N:1][C:2]2[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=2[CH:13]=1
Reactant: CCOC=C(C)C=O
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: Cc1cnc2c(c1)C(=O)CC(C)(C)C2
Yield: 60.8 %

Procedure:
A mixture of 3-amino-5,5-dimethylcyclohex-2-enone (27.8g., 0.2 mol.) and 2-methyl-3-ethoxyacrolein (22.8 g., 0.2 mol.), in an apparatus equipped for downward distillation, was heated in an oil bath at 120° until the theoretical quantity of distillate was collected (13 ml.) The cooled residue was diluted with 2N HCl (50 ml.), extracted with ethyl acetate (3 × 50 ml.) and the combined extracts discarded. The aqueous solution was adjusted to pH 9.0 with sodium carbonate and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled to give the title compound as a colourless oil (23 g., 53%) b.p. 83°/0.2 mm Hg. (RT = 2 min., 2% OV17, T=150° C).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[OH-:12].[Na+]>[Cu].O>[OH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: [OH-]
Agent: [Cu]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccccc1O
Temperature: 25 °C
Yield: 93 %

Procedure:
`Isopar M` (500 ml), (2-chlorophenyl)acetic acid (51.3 g, 0.3M), copper II sulphate hexahydrate (2.88 g, 10 mM) and sodium hydroxide pellets (84 g, 2.1M) were changed to a 1.5 litre hastalloy vessel equipped with a stirrer and condenser. The temperature of the vessel was increased from ambient using an oil bath, while stirring the reaction mixture. The oil bath was maintained at between 210° C. and 220° C. for 6 hours and then heating was ceased and the vessel was allowed to cool to ambient temperature. Water (500 ml) was added (exothern) and the reaction mixture was stirred for a further 30 minutes. After filtering off some insoluble material (about 600 mg) the phases were separated and the upper organic phase set aside (480-490 ml). The aqueous phase was acidified to pH1 (by test paper) by adding 36% hydrochloric acid (125-155 ml, exothern), and then extracted with isopropyl acetate (2×250 ml). The combined isopropyl acetate extracts were evaporated at 60° C. and about 20 mm Hg on a rotary evaporator to give (2-hydroxyphenyl)acetic acid as brown solid (44-45 g, purity by gas chromatography 94-99%, yield 93-96%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>Cl>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:20]([C:19]([F:24])([F:23])[F:18])[NH:9][C:5]2=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17]
Reactant: Nc1cc(-c2cccc(Cl)c2Cl)c(Cl)nc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: FC(F)(F)c1nc2nc(Cl)c(-c3cccc(Cl)c3Cl)cc2[nH]1

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59%). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33% ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97%). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75%). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2%).
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:15]([O:16][CH2:17][CH2:18][N:19]=[N+]=[N-])[C@H:14]2[OH:28])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>O.CO.[Pd]>[C@H:1]1([O:12][C@H:13]2[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:28])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 50 mL round bottom flask, 2-azidoethyl 3-O-α-D-mannopyranosyl-α-D-mannopyranoside (139 mg, 0.338 mmol) was dissolved in water/CH3OH (v/v 1:1, 5 mL). To the above solution was added Pd/C (10%, 36 mg, 0.034 mmol). The reaction mixture was stirred at 25° C. under H2 balloon for 18 hr. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the title compound. LC-MS Method A: m/e=386.08 [M+1]; Rt=0.24 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH:16](N)=[NH:17]>>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[N:11]=[CH:16][NH:17][C:7]2=[O:9]
Reactant: N=CN
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Agent: Cl
Product: O=c1[nH]cnc2cc([N+](=O)[O-])c(Cl)cc12
Temperature: 205 °C
Reaction time: 0.67 h
Yield: 84.2 %

Procedure:
A mixture of 5-chloro-4-nitroanthranilic acid (8.7 g, 0.040 mol) and formamidine hydrochloride (4.9 g, 60 mmol) were ground to a fine, intimate powder using a mortar and pestle. The mixture was transferred into a 250 mL round bottomed flask and immersed in an oil bath maintained at 205° C. After 40 min, LCMS analysis of the reaction mixture showed mass corresponding to the product. The reaction mixture was cooled and the crude product was crushed into pieces and washed several times with saturated NaHCO3 (300 mL) and water (200 mL). The solid was air dried and triturated with a minimum amount of MeOH (20 mL) to obtain 6-chloro-7-nitroquinazoline-4-one (7.6 g, 83%) as a tan powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)O)C2)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of (3S)-1-(2-amino-6-chloro-4-pyrimidinyl)-3-piperidinecarboxylic acid (1.9 g, 7.40 mmol), (4-cyano-3-fluorophenyl)boronic acid (1.465 g, 8.88 mmol) and NaHCO3 (0.622 g, 7.40 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was stirred for 10 minutes under nitrogen. Pd(Ph3P)4 (0.171 g, 0.148 mmol) was added, and the microwave tube was heated at 140° C. for 50 minutes in microwave. LCMS showed 50% desired product. The reaction was then heated at 100° C. overnight. The yellow mixture was filtered and dried. The solid was washed with Et2O (3×), and dried. The filtrate was poured into water. The formed solid was filtered and dried. The solids were combined to afford the title compound (1.8 g) as a yellow solid. LC-MS (ES) m/z=342 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 4-(5-Bromo-pyridin-2-yloxy)-benzaldehyde (RH3-A02640-038) (3.501 g, 12.6 mmol) in 1,2-dichloroethane (61 mL) is added isoamylamine (1.65 mL, 14.2 mmol), NaBH(OAc)3 (4.00 g, 18.9 mmol), and acetic acid (1.10 mL, 19.2 mmol). The reaction is stirred overnight. The reaction mixture is then washed with saturated NaHCO3 (2×100 mL), dried over MgSO4, filtered, and concentrated. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 25% of ethyl acetate to 100% of ethyl acetate to give [4-(5-Bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (2.18 g, 50%) as a yellow oil. 1NMR (400 MHz, CDCl3) δ ppm: 8.21 (d, J=3.1 Hz, 1H), 7.75 (dd, J=2.6, 8.7 Hz, 1H), 7.37-7.34 (m, 2H), 7.09-7.05 (m, 2H), 6.82 (d, J=9.1 Hz, 1H), 2.49 (s, 2H), 2.66 (dd, J=7.6, 7.6 Hz, 2H), 1.67-1.61 (m, 1H), 1.44-1.38 (m, 2H), 1.15 (s br, 1H), 0.90 (d, J=6.6 Hz, 6H); MS (ES): [M+H]+ found 261.7.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)cc2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(Cl)cc2)n1
Yield: 59.5 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-amine (653 mg, 2.62 mmol) and phenyl chloroformate (1.0 mL, 7.85 mmol) were reacted to give phenyl 3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-ylcarbamate (575 mg, 1.56 mmol, 59%). 1H NMR (300 MHz, DMSO-d6) δ 10.19 (br s, 1H), 7.63-7.60 (m, 4H), 7.39-7.36 (m, 2H), 7.23 (t, 1H), 7.06 (br s, 2H), 6.38 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [Cl-].[Li+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].N12CCCN=C1CCCCC2.[C:29]([N:36]1[CH2:41][CH2:40][CH:39]([CH:42]=O)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[F:9]/[C:8](=[CH:42]/[CH:39]1[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:37][CH2:38]1)/[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)/C(F)=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 9 was prepared using the methods described in Scheme AE. Intermediate AE1 was prepared as follows. Lithium chloride (0.39 g) was added to a solution cooled to 0° C. of triethyl-2-fluoro-2-phophonoacetate (1.84 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.15 mL) in acetonitrile (6 mL). The mixture was stirred until the lithium chloride was dissolved to form a homogeneous solution. N-Boc-piperidine-4-carboxaldehyde (1.61 g) in acetonitrile (2.0 mL) was added to the mixture and stirred for 24 h at room temperature. The reaction was quenched with saturated ammonium chloride (20 mL), diluted with ethyl acetate (150 mL), and washed with saturated sodium chloride (50 mL). The organic layer was dried (magnesium sulfate) and evaporated to yield 2.27 g of (E)-ethyl 2-fluoro-3-(N-Boc-piperdin-4-yl)propenoate (AE1). AE1 was carried forward as shown in Scheme AA to afford 9. Compound 9 was isolated as white flakes: mp 147-150° C.; MS m/e 515 (MH+). Anal. calcd. for C25H31FN6O5•2.3 HCl•1.6 H2O (627.25): C, 47.88; H, 5.87; N, 13.40; Cl, 13.00. Found: C, 48.26; H, 6.02; N, 12.90; Cl, 12.74.