Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])C.[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH2:24])[CH3:23].C(OCC)(=O)C>CCCCCC>[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH:24][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])[CH3:23]
Reactant: CCOc1c(Nc2c(O)cccc2C#N)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1c(Nc2c(O)cccc2C#N)c(=O)c1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.250 g, 0.00097 mol) and (R)-2,2,1-trimethylpropylamine (0.2M in ethanol, 9.7 ml, 0.0019 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The reaction is evaporated on a rotary evaporator. The residue is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether with several drops of ethyl acetate to give 3-[(R)-2,2,1-trimethylpropylamino]-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.230 g (0.00073 mol, 76%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:2].Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[CH:38]([OH:48])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][C:33]=4[CH:38]([OH:48])[CH2:39][CH2:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: OC(CCCc1ccccc1)c1cnccc1Br
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4ccncc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester and 1-(4-bromo-pyridin-3-yl)-4-phenyl-butan-1-ol.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1>C(O)CCC>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([N:28]5[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]5)=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C1CCNC1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C(O)C1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 120 °C
Yield: 39.3 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline, (350 mg, 1.03 mmol), potassium carbonate (436 mg, 3.16 mmol), and 3-pyrrolidine carboxylic acid (236 mg, 2.05 mmol) in n-butanol (10.0 mL) was heated in the microwave at 120° C. for 60 minutes. The reaction mixture was cooled to room temperature, filtered, rinsed with ethyl acetate, and the filtrate was concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform containing 0.1% acetic acid/methanol (0.5-7%) to afford 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidine-3-carboxylic acid (152 mg, 39%).
Reaction SMILES: [N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:17]1([SiH3])[CH:22]=[CH:21][CH:20]=[CH:19]C=1.C1C23CC12C3>CC(O)C.ClCCl.CCCCC.CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.[Mn]>[C:20]12([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:2][C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:19][CH:22]([CH2:21]1)[CH2:17]2
Reactant: [SiH3]c1ccccc1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Mn]
Agent: C1C23CC12C3
Agent: CC(C)(C)C(=O)/C=C(\O)C(C)(C)C
Solvent: ClCCl
Solvent: CCCCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C12CC(C1)C2
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (281 mg, 0.460 mmol) was dissolved in 2-propanol (100 mL) in a 1 L 3-necked flask equipped with addition funnel, gas inlet, and thermometer. The solution was cooled to −15° C. under nitrogen. Di-tert-butyl azodicarboxylate (8.11 g, 34.5 mmol) and phenylsilane (2.9 mL, 23 mmol) were dissolved in dichloromethane (100 mL) and this resulting orange solution was added to the above cooled solution dropwise over 10 minutes, maintaining the internal temperature at approximately −10° C. A solution of [1.1.1]propellane (Journal of the American Chemical Society (2001), 123(15), 3484-3492) (50 mL, 23 mmol, 0.46 M in pentane) was added to the reaction mixture in one portion at −15° C. The reaction was stirred at −15° C. for 30 minutes. The cold bath was removed and the reaction was allowed to warm to room temperature and stir for 4 hours. The reaction was concentrated and purification by flash column chromatography (5-20% ethyl acetate/heptanes) gave the title compound (6.38 g, 93%) as a clear oil which solidified upon standing. −ESI (M−H) 297.4; 1H NMR (400 MHz, CDCl3, δ): 6.26 (br. s., 1H), 2.37 (s, 1H), 2.02 (s, 6H), 1.45 (s, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH:8]([OH:19])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.I[CH3:23]>ClCCl>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH:8]([O:19][CH3:23])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1nc2c(s1)C(O)COc1ccc(Br)cc1-2
Reactant: CI
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C(OC)COc1ccc(Br)cc1-2
Reaction time: 3 h
Yield: 28.9 %

Procedure:
A suspension of ethyl 9-bromo-4-hydroxy-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (500 mg, 1.35 mmol, 1.00 equiv), Ag2O (1.247 g, 4.00 equiv), and iodomethane (763 mg, 5.38 mmol, 4.00 equiv) in dichloromethane (5 mL) was stirred for 3 h at 50. The reaction was quenched with 10 mL of brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:20) to give 150 mg (29%) of the titled compound as a white solid; LC-MS (ES, m/z) 384, 386[M+H]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To a stirred mixture of Compound 264B (530 mg, 1.50 mmoL) in 6 mL of THF and 1 mL of water was added Ph3P (900 mg, 3.43 mmoL). The reaction mixture was heated at 70° C. for 15 h and cooled to room temperature. This mixture was concentrated in vacuo, diluted with 15 mL of 2N HCl solution, and then washed with CHCl3 (3×20 mL). The aqueous was basified to pH 12 by the addition of 50% NaOH solution, saturated with NaCl, and then extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to give 490 mg (yield: 100%) of Compound 264C. It had an analytical HPLC retention time=1.67 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=328.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[Na+].[I-].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][C:22]=1[F:29]>C(#N)C>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:8]2[CH:7]=[C:6]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:5]=[CH:4][C:3]2=[O:2])=[CH:23][C:22]=1[F:29]
Reactant: COc1ccc(-c2nc3ccccc3s2)cn1
Reactant: Fc1cc(CBr)ccc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1ccc(-c2nc3ccccc3s2)cn1Cc1ccc(Cl)c(F)c1
Temperature: 90 °C
Reaction time: 14 h
Yield: 56 %

Procedure:
According to Scheme 4, Step 1: A mixture of 2-(6-methoxypyridin-3-yl)benzo[d]thiazole (1 eq, 0.25 mmol, 60 mg), NaI (5 eq, 1.20 mmol, 0.19 g) and 4-chloro-3-fluorobenzylbromide (5 eq, 1.20 mmol, 0.28 g) in acetonitrile (10 mL) was stirred for 14 hours at 90° C. The crude residue was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 95/5 as eluent to afford 1-(4-chloro-3-fluorobenzyl)-5-(benzo[d]thiazol-2-yl)pyridin-2(1H)-one (0.14 mmol, 0.05 g, 58%) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[NH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:23][C:24]1[C:40](F)=[CH:39][CH:38]=[C:37]([N+:42]([O-:44])=[O:43])[C:25]=1[O:26][C:27]1[CH:28]=[C:29]([C:35]#[N:36])[CH:30]=[C:31]([CH:34]=1)[C:32]#[N:33].O>C1COCC1.CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:40]1[CH:39]=[CH:38][C:37]([N+:42]([O-:44])=[O:43])=[C:25]([O:26][C:27]2[CH:28]=[C:29]([C:35]#[N:36])[CH:30]=[C:31]([C:32]#[N:33])[CH:34]=2)[C:24]=1[F:23])[C:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[NH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)n[nH]c1=O
Reactant: N#Cc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])c(Oc3cc(C#N)cc(C#N)c3)c2F)n[nH]c1=O
Temperature: 0 °C
Reaction time: 19 h
Yield: 62.4 %

Procedure:
A 5 L three-neck round bottom flask was charged with (5-methyl-6-oxo-1,6-dihydro-pyridazin-3-3-yl)-acetic acid tert-butyl ester (10; 223 g, 0.996 mol) and THF (700 mL). The resulting solution was cooled to 0° C. and potassium tert-butoxide (1.2 L, 1.66 M in THF, 1.99 mol) was added dropwise over approximately 30 min. After cooling the reaction mixture to −55° C., a solution of 5-(2,3-difluoro-6-nitro-phenoxy)-isophthalonitrile (22; 150 g; 0.498 mol) in THF (1.0 L) was added dropwise over approximately 1 h. Following a THF rinse (500 mL), the cooling bath was removed, and the reaction mixture was stirred for 19 h with warming to ambient temperature. The reaction mixture was then quenched by the addition of 1N HCl (1.75 L). Following removal of the aqueous layer (2 L, pH of 3-4) the organic phase was washed with water (1.0 L) and brine (750 mL). The resulting THF solution was filtered through CELITE® and the filter aid washed with THF (500 mL). The solution was then concentrated in vacuo to afford a dark oil which was dissolved in NMP (850 mL) and warmed to approximately 50° C. Water (425 mL) was added dropwise. The cloudy solution was stirred slowly, seeded with a crystal and cooled to 0° C. After stirring at 0° C. for 30 min, the product was filtered. The filter cake was then washed with MeOH (100 mL, 200 mL) and dried in a vacuum oven (50° C., 25 Torr) to afford [3-(3,5-dicyano-phenoxy)-2-fluoro-4-nitro-phenyl]-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl ester (23; 157 g, 62% theory).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:13]([C:12]2[C:11]([Cl:10])=[N:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNC(=O)c1ccc[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CNC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
To a mixture of 1H-pyrrole-2-carboxylic acid methylamide (430 mg, 3.5 mmol) and 2-chloronicotinoyl chloride (0.6 g, 3.4 mmol) in benzene (15 mL) at 0° C. was added a dropwise solution of tin (IV) chloride (1.6 g) in benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for 4 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried and concentrated to give 320 mg (35%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid methylamide.
Reaction SMILES: C(S(C)(=O)=O)=C.[CH3:7][S:8]([CH2:11][CH2:12][N:13]1[CH:18]2[CH2:19][CH2:20][CH:14]1[CH2:15][CH:16]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=1)[CH2:17]2)(=[O:10])=[O:9].[N+](C1C=CC(OC2CC3NC(CC3)C2)=CC=1)([O-])=O>CO>[CH3:7][S:8]([CH2:11][CH2:12][N:13]1[CH:14]2[CH2:20][CH2:19][CH:18]1[CH2:17][CH:16]([O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=1)[CH2:15]2)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)CCN1C2CCC1CC(Oc1ccc([N+](=O)[O-])cc1)C2
Agent: C=CS(C)(=O)=O
Agent: O=[N+]([O-])c1ccc(OC2CC3CCC(C2)N3)cc1
Solvent: CO
Product: CS(=O)(=O)CCN1C2CCC1CC(Oc1ccc(N)cc1)C2
Temperature: 60 °C

Procedure:
8-(2-Methanesulfonylethyl)-3-(4-nitrophenoxy)-8-azabicyclo[3.2.1]octane Methyl vinyl sulfone (585.9 mg) was added to a solution of 3-(4-nitrophenoxy)-8-azabicyclo[3.2.1]octane (1.0 g) in methanol (3.7 ml) and heated at 60° C. for 12 h. The solvent was then removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was washed with water and dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 9:1). The product with the molecular weight of 354.42 (C16H22N2O5S) was obtained in this way; MS (ESI): 355 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:15]([O:19][C:20](=[O:31])[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:26][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 0.25 h
Yield: 24157.4 %

Procedure:
Entire reaction was performed under dry air using syringe septa technique. 4 Å molecular sievies were added to a stirred solution of 4-chloro-3-(trifluoromethyl)phenylboronic acid (5.00 g, 0.022 mmol) and [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert butyl ester (2.64 g, 0.051 mol, 2 eq) in dry DCM (120 ml) at ambient temperature in a flame dried flask flushed with dry air. The reaction was stirred for 15 min. After that, copper (II) acetate (5.33 g, 0.010 mol, 1.3 eq), triethylamine (7.34 ml, 0.052 mol, 5 eq) and pyridine (4.25 ml, 0.052 mol, 5 eq) were added in succession and the reaction was stirred for 50 hours. The reaction mixture was sequential washed with 0.5 M HCl (4×250 ml), water (3×150 ml) and brine (1×150 ml). Organic layers were combined, dried over Na2SO4/MgSO4, filtered and evaporated. Crude product was purified on Biotage SP1 Snap Si 100; 40 ml/min in the gradient of EtOAc in Cyclohexan: 0-30% in 25 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product {2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2.21 g, yield=24%, purity=82%). [M+H]+=416.84 [M+H-56]+=360.27 1H NMR (300 MHz; CDCl3) δ/ppm 1.50 (s, 9H), 2.85 (t, J=6.97 Hz, 2H), 3.38-3.48 (m, 2H), 4.63 (br. S., 1H), 7.01 (d, J=8.57 Hz, 2H), 7.11 (dd, J=8.77, J=2.79 Hz, 1H), 7.25 (d, J=8.57 Hz, 2H), 7.36 (d, J=2.79 Hz, 1H), 7.47 (d, J=8.77 Hz, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([C:12](=C(C)C)[OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2].C(O)C>O.Cl>[CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2]
Reactant: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)C(O)=C(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Yield: 83 %

Procedure:
12.4 g of the 3-O-ethyl-isopropylidene ascorbic acid obtained in Example 1 was dissolved in 100 ml of distilled water, to which 10 ml of 2N hydrochloric acid solution was added. The mixture was reacted at 60° C. for 2 hours and concentrated under reduced pressure to give an adhesive liquid product. Ethanol was added to the prepared liquid product, which was then concentrated to give crude crystalline 3-ethyl-ascorbic acid. The crude crystalline 3-ethyl-ascorbic acid was re-crystallized in ethylacetate/ethanol (8:2) to give 8.6 g of white crystalline 3-O-ethyl-ascorbic acid (yield: 84.3%).
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([C:8]2[CH:34]=[CH:33][C:11]([O:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]5[N:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:23][CH2:22]4)[N:16]=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:4][O:3]1>CC(C)=O>[CH3:19][C:18]1[C:13]([O:12][C:11]2[CH:33]=[CH:34][C:8]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:9][CH:10]=2)=[N:14][CH:15]=[N:16][C:17]=1[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1
Reactant: Cc1c(Oc2ccc(C3COC(C)(C)OC3)cc2)ncnc1OC1CCN(c2ncccn2)CC1
Solvent: CC(C)=O
Product: Cc1c(Oc2ccc(C(CO)CO)cc2)ncnc1OC1CCN(c2ncccn2)CC1
Temperature: 27 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of 4-(4-(2,2-dimethyl-1,3-dioxan-5-yl)phenoxy)-5-methyl-6-(1-(pyrimidin-2-yl)piperidin-4-yloxy)pyrimidine (1.5 gm, 0.0031 moles) in acetone (20 ml) conc. HCl (2 ml) was added portion-wise and the reaction mixture was stirred for 3 hours at 27° C. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 700 mg product as white solid
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:19]1([CH2:18][CH2:17][CH2:16][CH:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)C(CCCc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(O)C(CCCc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (±)-2-(4-fluoro-benzenesulfonylamino)-5-phenyl-pentanoic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=59-62° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:7]([C:8]3[CH:9]=[C:10]4[C:14](=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:16]=3)[NH:13][N:12]=[CH:11]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][C:23]=1[CH3:31]
Reactant: COC(=O)c1cc(-c2cccnc2Cl)cc2cn[nH]c12
Reactant: Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccnc2-c2ccc(F)c(C)c2)cc2cn[nH]c12
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A single necked round bottom flask (100 mL) equipped with a magnetic stirring bar was charged with methyl 5-(2-chloropyridin-3-yl)-1H-indazole-7-carboxylate (0.88 g, 3.0 mmol), 4-fluoro-3-methylphenyl boronic acid (0.56 g, 3.63 mmol), PdCl2(PPh3)4 (214 mg g, 1.0 mmol), 1,4-dioxane (75 mL) and 2M aq. Na2CO3 (4.2 mL, 8.4 mmol mL) under argon atmosphere. The rubber septum was replaced with reflux condenser containing three-way stopcock. The system was then evacuated three times and back filled with argon and externally heated at 100° C. (oil bath) for 48 h. The heterogeneous reaction mixture was allowed to cool to room temperature and concentrated under vacuum to remove the volatiles by rotary evaporator. The crude concentrate flask was charged with chloroform (100 mL)/water (30 mL) and stirred. Organic layer was separated and the aqueous layer further extracted with chloroform (75 mL). Combined organic layers were stirred over MgSO4/Celite® for 20 min, suction filtered and filter cake washed with chloroform (30 mL). The filtrate collected was concentrated and purified by silica gel flash chromatography [Combiflash® companion System® with RediSep® silica gel column (24g), solvent eluent gradient 30-50% EtOAc/hexanes] to obtain methyl 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylate (420 mg, 39%) as a white solid. 1H NMR (DMSO-d6): δ 13.1 (s, 1H), 8.62 (dd, 1H, J=0.5 and 4.7 Hz), 8.04 (s, 1H), 7.83 (d, 1H, J=7.6 Hz), 7.66 (s, 1H), 7.45-7.34 (app m, 3H), 7.02 (d, 1H, J=8.5 Hz), 6.96-6.85 (m, 2H), 2.11 (s, 3H). 19F NMR (DMSO-d6): δ −118.91. LCMS: rt 5.23 min (A), purity 93%,MS (m/e) 362 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.[NH3:17]>>[NH2:17][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Reactant: N
Product: Nc1nc(N)c2ncn(COCCO)c2n1
Temperature: 120 °C
Yield: 12 %

Procedure:
A mixture of 2-chloro-9-(2-hydroxyethoxymethyl)adenine (4.4 g) and liquid ammonia (40 ml) was heated at 120° C. in a bomb for 19 hours. The reaction mixture was removed from the bomb and excess ammonia removed in vacuo. The residue was partitioned between ether and water and the aqueous layer washed twice more with ether and once with chloroform. The aqueous solution was then treated with an excess of a strongly basic ion exchange resin to convert the ammonium chloride to ammonia and evaporated to dryness in vacuo. The residue was dissolved in a minimal amount of ethanol, Florisil (Registered Trade Mark) (10 g) added, and the mixture evaporated in dryness. The residue was transferred to a prepared column of Florisil in chloroform and eluted with 5% methanol/95% chloroform (v/v). Fractions (30 ml) were collected and examined by TLC (silica gel plates developed in 10% methanol/90% chloroform) for the presence of product. The first 40 fractions contained starting material but no product and were discarded. Succeeding fractions which were found to contain the desired product were combined and evaporated to dryness. The residue was recrystallized from ethanol (with activated charcoal treatment) and from n-propanol to give 2-amino-9-(2-hydroxyethoxymethyl) adenine (0.5 g, 12% of theoretical), m.p. 183°-184° C.