Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C@H:13]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])C)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:19]([C@H:13]1[N:12]([C:10](=[O:11])[C@H:9]([NH:7][CH3:6])[CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:17][CH2:16][NH:15][C:14]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCNC(=O)[C@H]1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCNC(=O)[C@H]1Cc1ccccc1
Yield: 93.1 %

Procedure:
N-((1R)-2-((2R)-2-Benzyl-3-oxopiperazin-1-yl)-1-((2-naphthyl)methyl)- 2-oxoethyl)-N-methylcarbamic acid tert-butyl ester (0.405 g; 0.808 mmol) was dissolved in methylene chloride (5 ml) and trifluoroacetic acid (5 ml) and stirred 10 min at room temperature. Water (10 ml) and sodium hydrogencarbonate were added to pH 8. The reaction mixture was extracted with methylene chloride (2×30 ml), dried over magnesium sulfate and evaporated in vacuo to afford 0.302 g of (3R)-3-benzyl-4-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperazin-2-one.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][CH2:24][C:25]([O:27]CC)=O)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7]>O>[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][CH2:24][C:25]([NH2:5])=[O:27])[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(N)=O
Temperature: 125 °C
Reaction time: 8 h

Procedure:
Ammonium acetate (7 g) and ethyl 3-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (5.0 g, 15 mmol, prepared in Part A of Example 23) were stirred overnight at 125° C. in a sealed vessel. The reaction was allowed to cool to ambient temperature, and water (20 mL) was added. A precipitate formed and was isolated by filtration, washed with saturated aqueous sodium bicarbonate, and dried to provide 2.4 g of 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propanamide as a tan powder.
Reaction SMILES: CO.C(O)(C)C.[OH-].[K+].[C:9](I)([C:12]([C:15]([C:18]([C:21]([C:24]([F:27])([F:26])[F:25])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10]>[Cr].[Co].O>[CH:9]([C:12]([C:15]([C:18]([C:21]([C:24]([F:25])([F:26])[F:27])([F:22])[F:23])([F:19])[F:20])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Co]
Agent: [Cr]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Into a 20 l Hastelloy C autoclave equipped with a stirrer, a reflux condenser and a thermometer, 5130 g of methanol and 60 g of isopropyl alcohol and 1485 g (22.5 mols) of 85% potassium hydroxide were charged. The reactor was heated to bring the internal temperature to 50° C. Then, 4460 g (10 mols) of C6F13I was fed thereto over a period of two hours. While maintaining the internal temperature of the reactor at a level of from 50° to 55° C. stirring was continued for 10 hours. The conversion was more than 99.9%. The reactor was cooled to room temperature, and then, 3200 g of water was added to dissolve precipitated potassium iodide. The crude reaction solution was separated into two layers, and the fluorocarbon layer (lower layer) was further washed twice with 3200 g of water to obtain 2975 g (purity: 99.9%) of C6F13H. In the reactor, no formation of tar was observed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Br)ccc1O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Br)ccc1O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
4-(Trifluoromethyl)benzoic acid (1 g, 5.3 mmol) dissolved in DCM (10 ml), cooled to 0° C. and added oxalyl chloride (0.7 ml, 7.9 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Amino-4-bromophenol (0.8 g, 4.25 mmol) dissolved in DCM (20 ml) and added Pyridine (0.4 ml, 5.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (1.06 g, 5.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.15 (bs, 1H), 9.75 (s, 1H), 8.13 (d, J 8.1, 2H), 7.92-7.87 (m, 3H), 7.20 (dd, J 2.5, 8.6, 1H), 6.88 (d, J 8.6, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1cc(F)cc(F)c1
Yield: 85.3 %

Procedure:
Step AL (1): 2-(3,5-Difluorophenyl)acetic acid (2.5 g, 14.5 mmol) was deprotonated with NaHMDS (1.0 M in THF, 29.0 mL, 29.0 mmol) and reacted with 1-chloro-4-iodobutane (1.78 mL, 14.5 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(3,5-difluorophenyl)hexanoic acid (3.25 g, 85% yield). LC-MS (m-H)− 261.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.CCN(C(C)C)C(C)C.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>C(Cl)Cl>[Cl:34][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:21]([CH2:20][C@@H:19]([NH:18][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[O:8])[CH3:35])[N:22]=2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc[nH]n1
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a mixture of 1H-pyrazole-3-carboxylic acid (89 mg, 0.767 mmol) in DCM (5 ml), was added DIPEA (0.40 ml, 2.30 mmol). O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniutnhexafluorophosphate (HBTU, 291.0 mg, 0.767 mmol) at RT. The mixture was stirred for 15 min and solid (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) was added. The reaction was stirred overnight at RT. The solvent was evaporated and water was added. The pH of the water phase was adjusted to 9-10 and the product was extracted to DCM. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated. The crude product was purified with flash chromatography (DCM/EtOAc gradient) to give title compound 100 mg. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 4.36 (m, 3H), 6.58 (t, 1H), 6.93 (d, 1H), 7.79 (m, 1H), 7.82 (d, 1H), 7.98 (d, 2H), 8.08 (bs, 1H), 8.25 (d, 1H), 13.20 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6]OCC)[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:14])[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[S:10]([CH3:13])(=[O:11])=[O:12])=[CH:17][CH:18]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OCC)S(C)(=O)=O
Product: CCOC(=O)C(=CNc1ccc(C(=O)OCC)cc1)S(C)(=O)=O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
The compound of 3-ethoxy-2-methanesulfonyl-acrylic acid ethyl ester (example 61c, 52 g, 0.234 mol) and aniline (38.65 g, 0.234 mol) was mixed and heated at 140-150° C. under stirring for two hours. After cooling the reaction to room temperature, solvent was removed to give 4-(2-ethoxycarbonyl-2-methanesulfonyl-vinylamino)-benzoic acid ethyl ester. The crude compound was used in the following reaction without further purification. LC-MS m/e 342 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH3:31].O>CN(C)C=O>[CH2:30]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:31]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (32 mg, 0.098 mmol) in 1 mL of dimethylformamide was added cesium carbonate (95 mg, 0.29 mmol) and iodoethane (0.0094 mL, 0.12 mmol). After one hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C15H20N3O5S (M+H+): 354.1118. Found 354.1094.
Reaction SMILES: N1CCC(C(OC([C:12]2[CH:13]=[N:14][C:15]([N:18]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[F:30])=[N:16][CH:17]=2)C)=O)CC1.[OH-].[Na+].Cl.[C:49]([O:52]CC)(=[O:51])[CH3:50]>C(O)C>[F:45][C:42]([F:43])([F:44])[C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=1)[CH2:31][N:18]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=1[F:30])[C:15]1[N:16]=[CH:17][C:12]([N:18]2[CH2:31][CH2:32][CH:50]([C:49]([OH:52])=[O:51])[CH2:20][CH2:19]2)=[CH:13][N:14]=1
Reactant: CCOC(C)=O
Reactant: CC(OC(=O)C1CCNCC1)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)Cc3cc(C(F)(F)F)ccc3F)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-{2-[(3,5-Bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-carboxylate (105 mg) is dissolved in ethanol (4 ml) and thereto is added a 1N-aqueous sodium hydroxide solution (2 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 1-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-piperidine-4-carboxylic acid (81 mg). MS (m/z): 625 [M+H]+
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17](I)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=3)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1nccc2c1c(I)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (30.0 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (25.8 mg), tetrakis(triphenylphosphine)palladium(0) (7.13 mg) and potassium carbonate (17.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.1 mg).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:23]1[S:24][C:25]2[C:30]([N:31]=1)=[CH:29][CH:28]=[CH:27][N:26]=2.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[K+]>CN(C=O)C.C(O)(C)C.O>[N:31]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[S:24][C:23]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[CH:20][CH:21]=1
Reactant: Clc1nc2cccnc2s1
Reactant: CCOC(=O)C1CCN(CCOc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(CCOc2ccc(Oc3nc4cccnc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a stirred solution of ethyl 1-[2-(4-hydroxyphenoxy)ethyl]piperidine-4-carboxylate (400 mg, 1.37 mmol) and 2-chloro[1,3]thiazolo[5,4-b]pyridine (231 mg, 1.37 mmol) in DMF (6 mL) was added Cs2CO3 (887 mg, 2.73 mmol). The resultant dark red-orange suspension was stirred at rt for 1 h. The reaction mixture was concentrated, and the residue re-dissolved in CH2Cl2 (10 mL) and filtered. To a solution of this crude material in isopropyl alcohol was added 1 N KOH (1 equiv.). The mixture was allowed to stir at rt for 2 h and then poured into water and basified to pH 9. The resultant solution was extracted with a 1:1 solution of CHCl3/isopropyl alcohol. The combined organic extracts were dried, filtered, and concentrated to afford the title compound (39% over two steps). 1H NMR (400 MHz, DMSO-d6): 8.43 (dd, J=4.8, 1.5, 1H), 8.07 (dd, J=8.2, 1.5, 1H), 7.50 (dd, J=8.2, 4.8, 1H), 7.44-7.34 (m, 2H), 7.10-7.04 (m, 2H), 4.11 (t, J=5.8, 2H), 2.94-2.82 (m, 2H), 2.70 (t, J=5.8, 2H), 2.27-2.15 (m, 1H), 2.15-2.04 (m, 2H), 1.85-1.71 (m, 2H), 1.64-1.47 (m, 2H). MS (ESI): mass calcd. for C20H21N3O4S, 399.13; m/z found, 400.1 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:25]1[CH:30]=[CH:29][N:28]2[N:31]=[CH:32][CH:33]=[C:27]2[N:26]=1.C(O)(C)C>CCOCC>[F:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][CH:33]=[C:27]3[N:26]=2)[CH:4]=1
Reactant: Oc1ccc(F)cc1[C@H]1CCCN1
Reactant: Clc1ccn2nccc2n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(F)cc1[C@H]1CCCN1c1ccn2nccc2n1
Temperature: 120 °C
Yield: 88.5 %

Procedure:
A mixture of (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride (Example 20, Step B, 1.50 g, 6.89 mmol), DIEA (2.67 g, 20.7 mmol), 5-chloropyrazolo[1,5-a]pyrimidine (1.11 g, 7.24 mmol) and isopropanol (1 mL) was heated at 120° C. overnight. The reaction was poured into ether (50 mL) and extracted with NaOH (1N aqueous, 3×25 mL). The combined aqueous extracts were brought to pH 4 with concentrated HCl and extracted with DCM. The combined DCM extracts were filtered through phase separator paper and concentrated to provide (R)-4-fluoro-2-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol (1.82 g, 89% yield) as beige solid. MS (apci) m/z=299.4 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].CC(C)([O-])C.[K+].CS(O[CH2:18][C:19]1[C:24]([O:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:23][CH:22]=[CH:21][N:20]=1)(=O)=O>O1CCOCC1>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][CH2:27][CH2:26][O:25][C:24]1[C:19]([CH2:18][O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)OCc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)CCOCc1ncccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of 2-(N,N-dimethylamino)ethanol (0.84 g, 9.4 mmol) in dry dioxane (30 mL) was added potassium tert-butoxide (0.92 g, 8.2 mmol) and the mixture was stirred at room temperature for 20 minutes after which time a solution of {3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}methyl methanesulfonate (from Step 2; 2.1 g, 6.3 mmol) in dioxane (10 mL) was added. The initially slightly exothermic reaction was stirred at ambient temperature overnight. The solvent from the reaction mixture was evaporated under reduced pressure and the resulting oil was taken up between CHCl3/water. The aqueous phase was extracted once with CHCl3 and the combined organic phases were dried (MgSO4) and the solvent was again evaporated. The resulting oil was chromatographed on a column of silica (100 mm, i.d.=30 mm) with initially CHCl3 100% (100 mL) followed by CHCl3/MeOH/NH4OH (95:5:0.2; 100 mL, and thereafter 90:10:0.2) to give 0.74 g (36%) of the title compound as a brown oil. HRMS m/z calcd for C17H28N2O4 (M)+ 324.2049. found 324.2042.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:26](O)=[O:27]>>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=1)[CH:26]=[O:27]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (6.87 g, 30 mmol) and hexamethylenetetramine (20 g, 143 mmol) in trifluoroacetic acid (60 mL) was heated at 90° C. under nitrogen for 22 hours. The hot reaction mixture was poured into 1M aqueous hydrochloric acid (200 mL) and the mixture stirred vigorously for 6 hours. The resulting suspension was filtered to give 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (6.79 g, 88% yield) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:45][CH2:44][N:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:19]4[N:20](CC5C=CC(OC)=CC=5OC)[C:21](=[O:32])[C:22]([C:28]([O:30]C)=[O:29])=[C:23]([OH:27])[C:24]=4[CH2:25][CH3:26])=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=O)(C)(C)C.[I-].[Li+]>CCOC(C)=O>[CH2:25]([C:24]1[C:23]([OH:27])=[C:22]([C:28]([OH:30])=[O:29])[C:21](=[O:32])[NH:20][C:19]=1[C:15]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:44][CH2:45][NH:8][CH2:9][C:10]3=[CH:18][C:17]=2[CH:16]=1)[CH3:26]
Reactant: CCc1c(O)c(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc3c(c2)cc2n3CCNC2)[nH]c(=O)c(C(=O)O)c1O
Temperature: 60 °C
Yield: 21.2 %

Procedure:
To a solution of tert-butyl-8-(1-(2,4-dimethoxybenzyl)-3-ethyl-4-hydroxy-5-(methoxycarbonyl)-6-oxo-1,6-dihydropyridin-2-yl)-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (0.5 g, 0.8 mmol) in EtOAc (8 mL) was added lithium iodide (0.33 g, 2.4 mmol). The solution was heated at 60° C. for 1.5 h then cooled to room temperature and diluted with EtOAc (20 mL). The reaction mixture was washed with 1M HCl (20 mL), 10% Na2S2O3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated. To the crude residue was added TIPS-H (1 mL) and TFA (1 mL), and the reaction mixture was heated at 60° C. for 1 h. The reaction mixture was allowed to cool to room temperature and the solvents were removed in vacuo. To the crude residue was added HCl/Et2O (1 mL, 2.0 M) and the precipitate was collected by filtration to afford the title compound as a light brown solid (60 mg, 21%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][CH:27]=1)#[N:21]>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cccc(C#N)c2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Yield: 57 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-cyanophenylboronic acid pinacol ester with reaction time of 15 h. Column chromatography (hexane/ethyl acetate 1:1) gave 57% of the title compound as an colorless solid.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.C[Si](C)(C)[O:24][C:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:27][CH:26]=1>CC#N>[F:21][CH:30]1[C:25](=[O:24])[CH2:26][CH2:27][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:29]1
Reactant: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Selectfluor® (181.2 g, 511.4 mmol) was added portion-wise (about 25 g portions) to a ice cold solution of benzyl 4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (142 g, 465 mmol) in CH3CN (2 L) over approximately 30 minutes. The ice bath was removed and the mixture was allowed to stand for 12 hours. The mixture was concentrated to a slurry, diluted with EtOAc and brine and the layers were separated. The brine phase was extracted once with EtOAc, and the combined organic phases were washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the desired product as a dark thick oil (112 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([O:37][CH3:38])[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[O:37][CH3:38])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1cncc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-2-methoxy-phenylboronic acid, 5-(4-fluoro-2-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield=92%).