Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:9])#[N:2].[C:22]([O:26][C:27](N1CCC(NC(=O)C2C=C(OC)C=C(O)C=2)CC1)=[O:28])([CH3:25])([CH3:24])[CH3:23].BrCC#N.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:22]([O:26][C:27]([N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:5]([O:4][CH2:3][C:1]#[N:2])[CH:6]=2)[CH2:16][CH2:15]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1cc(O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COc1cc(OCC#N)cc(C(=O)NC2CCNCC2)c1
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCC#N)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 3-cyanomethoxy-5-methoxy-N-piperidin-4-yl-benzamide [prepared by i) reaction of 4-(3-hydroxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (example 168a) with bromo-acetonitrile in MeCN at rt in the presence of anhydrous potassium carbonate to give 4-(3-cyanomethoxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester; ii) Boc cleavage using trifluoro acetic acid (90%) in MeCl2 at rt in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 486.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:11]([CH3:23])[CH:10]=2)[C:3]=1[NH2:24].[I-:25].[Na+].O.C(=O)([O-])O.[Na+]>I.C(OCC)(=O)C>[IH:25].[I:25][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:11]([CH3:23])[CH:10]=2)[C:3]=1[NH2:24]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(Cl)c3N)cc2C)cn1
Reactant: [I-]
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Temperature: 70 °C
Yield: 95.3 %

Procedure:
6-Chloro-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine (400 mg) was suspended in 55% hydriodic acid (6.16 mL), sodium iodide (878 mg) was added, and the mixture was stirred with heating at 70° C. for 10 min. After cooling to room temperature, water (40 mL)/ethyl acetate (30 mL) was added. After adjusting its pH to not less than 7 with aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (626 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.[Cu][C:20]#[N:21].O>CN1C(=O)CCC1>[Cl:8][C:4]1[C:3]([C:9]2[S:10][C:11]3[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=3[N:17]=2)=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:20]#[N:21]
Reactant: N#C[Cu]
Reactant: Clc1cccc(Br)c1-c1nc2ccnc(Cl)c2s1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 150 °C
Yield: 28.9 %

Procedure:
A stirred mixture of 2-(2-bromo-6-chlorophenyl)-4-chlorothiazolo[5,4-c]pyridine (1.48 g, 4.11 mmol) and copper(I) cyanide (0.45 g, 5.0 mmol) in NMP (20 mL) was heated at 150° C. for 20 minutes. After cooling to room temperature, the mixture was poured into water (250 mL) and the insoluble material was collected by filtration. The solid was then suspended in EtOAc (300 mL) and, after vigorous stirring, was collected by filtration. The filtrate was concentrated under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 25-33% diethyl ether in pentane followed by 0-10% MeOH in DCM to afford the title compound as a pale yellow solid (0.364 g, 29% yield). LCMS (Method E): RT=3.59 min, m/z: 306 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:16]=[C:5]2[C:6]([N:10]3[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]3)=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.ClC1C2N(N=C(N)N=2)C=CN=1.N1CC[C@@H](O)C1.Cl[C:35]1[CH:43]=[C:42]2[C:38]([C:39]([CH3:46])([CH3:45])[C:40](=[O:44])[NH:41]2)=[CH:37][CH:36]=1>>[OH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:35]4[CH:43]=[C:42]5[C:38]([C:39]([CH3:46])([CH3:45])[C:40](=[O:44])[NH:41]5)=[CH:37][CH:36]=4)[N:16]=3)[CH:9]=[CH:8][N:7]=2)[CH2:11]1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Reactant: Nc1nc2c(N3CC[C@@H](O)C3)nccn2n1
Agent: Nc1nc2c(Cl)nccn2n1
Agent: O[C@@H]1CCNC1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(N5CC[C@@H](O)C5)nccn4n3)ccc21

Procedure:
(R)-1-(2-Amino-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-pyrrolidin-3-ol, synthesized by reaction of 8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and (R)-pyrrolidin-3-ol following general procedure 3, is coupled with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].COCCOC.[H-].[Na+].[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]Cl>O>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9]
Reactant: ClCCOCCOC1CCCCO1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)COCCOCCOC1CCCCO1
Reaction time: 1 h
Yield: 9.6 %

Procedure:
In a 2 liter-reaction vessel, 100 g (0.50M) of 2,2,3,3,4,4,4-heptafluorobutanol and 500 ml of ethylene glycol dimethyl ether were placed. To the mixture, 22 g (0.55M) of 60%-oily sodium hydride was added in 40 minutes at 10° C. or below, followed by stirring for 1 hour at the same temperature and stirring for 2.5 hours at room temperature. In a 1 liter-autoclave, the reaction mixture and 115.5 g (0.55M) of 2-chloroethoxyethyl tetrahydropyranyl ether were placed and stirred for 8 hours at 170° C. The above reaction was repeated three times, whereby 335 g in total of 2-chloroethoxyethyl tetrahydropyranyl ether was subjected to the reaction, followed by after-treatment of the reaction mixture for three times all together. More specifically, the reaction mixture for three times was poured into water all together and subjected to extraction with ethyl acetate, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel) to obtain 17.9 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above) and 354 g of a low-purity product thereof.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[CH3:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)=[CH:20][CH:19]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH3:17])=[CH:29][CH:28]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(OCCCCBr)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCOc1ccc(C)cc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
176.2 g of malonic acid diethyl ester are added dropwise at 50° C. to a sodium ethylate solution freshly prepared from 23 g of sodium and 500 ml of ethanol. The mixture is kept at this temperature for 2 hours, and 243.2 g of 4-(4-methylphenoxy)butyl bromide are then added dropwise. When the addition is complete, the obtained mixture is stirred at 60° C. for 3 hours, and substantially concentrated; 1 l of ice-water is then added and the mixture is extracted 3 times with a total of 1 liter of methylene chloride. The combined organic phases are dried over sodium sulfate, and the solvent and the excess malonic acid diethyl ester is distilled off in vacuo. 303.9 g of 4-(4-methylphenoxy)butylmalonic acid diethyl ester are obtained as pale yellow, oily residue.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 42%. Melting point: 202-205° C. (Ethyl acetate-hexane)
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(Br)cc1

Procedure:
The title compound was synthesized from methyl 4-(4-bromobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.0998 g, 0.3 mmol, 1 equiv) and lithium hydroxide (0.8 mL, 2 M aqueous, 1.6 mmol, 5.3 equiv), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (5 mL) was used. The resulting product was purified via preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 70% methanol and increasing to 100% over 7 minutes) afforded the title compound. 67.2 mg, with purity by HPLC of 100% (UV). LCMS m/e 318 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.02-2.16 (m, 1H), 2.49-2.67 (m, 3H), 2.74 (dd, J=9.77, 7.37 Hz, 2H), 3.19-3.29 (m, 1H), 6.29 (s, 1H), 7.11 (d, J=8.35 Hz, 2H), 7.41 (q, J=4.25 Hz, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:24]1([C:27]2[C:28](F)=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25]1>CS(C)=O.CCOC(C)=O>[CH:24]1([C:27]2[C:28]([O:17][C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][CH:13]=3)=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: Fc1ncccc1C1CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CC2)c1
Temperature: 125 °C

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (1.17 g, 4.81 mmol) in DMSO (40 mL) was added cesium carbonate (1.88 g, 5.78 mmol) and 3-cyclopropyl-2-fluoropyridine (660 mg, 4.81 mmol). The resulting mixture was heated to 125° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-(4-(3-cyclopropylpyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as tan solid. MS (ESI, pos. ion) m/z: 360.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH:26]12[CH2:31][CH:30]1[CH2:29][NH:28][CH2:27]2.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[C:16]([C:26]34[CH2:31][CH:30]3[CH2:29][NH:28][CH2:27]4)=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1
Reactant: C1NCC2CC12
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ccc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(C23CNCC2C3)c1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (compound 20b; 1.6 g, 4.2 mmol), 3-aza-bicyclo[3.1.0]hexane (1.00 g, 5.3 mmol), DIPEA (3.0 mL, 17 mmol) and dioxane (40 mL) at reflux (overnight).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16](OCC3C=CC([N+]([O-])=O)=CC=3)=[O:17])[CH:13]=[CH:14][C:3]1=2.[CH2:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH3:31].C(N(CC)CC)C>CCOC(C)=O.CN(C)C1C=CN=CC=1>[O:29]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:32]([CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:30][CH3:31])=[O:17])[CH:13]=[CH:14][C:3]1=2
Reactant: CCNCc1ccncc1
Reactant: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(Cc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Reaction time: 18 h

Procedure:
5,5-Dioxo-2-(4-nitrobenzoxycarbonylamino)dibenzothiophene (Example 24; 0.396 g, 1 mmol) was dissolved in EtOAc (10 ml) and treated with 4-(ethylaminomethyl)pyridine (0.150 g, 1.1 mmol), triethylamine (0.202 g, 2 mmol) and 4-(dimethylamino)pyridine (0.006 mg, 0.05 mmol). The reaction was stirred for 18 hours and the suspended solids collected, washed with 1 M aq. NaOH solution, water and then ether to leave the product as a colourless solid. NMR: 9.00 (s, 1H), 8.54 (m, 2H), 8.27 (s, 1H), 7.93 (m, 2H), 7.81 (m, 1H), 7.75 (m, 2H), 7.65 (m, 1H), 7.28 (m, 2H), 4.63 (s, 2H), 3.43 (q, 2H), 1.12 (t, 3H); m/z 394.42.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].N1CCCC1C(O)=O.[CH2:21]1[O:31][C:24]2([CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[O:23][CH2:22]1>C1(C)C=CC=CC=1>[O:23]1[C:24]2([CH2:29][CH2:28][CH:27]([CH:8]([S:5]([CH2:4][CH2:3][C:2]([F:1])([F:11])[F:12])(=[O:6])=[O:7])[C:9]#[N:10])[CH2:26][CH2:25]2)[O:31][CH2:21][CH2:22]1
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C(O)C1CCCN1
Solvent: Cc1ccccc1
Product: N#CC(C1CCC2(CC1)OCCO2)S(=O)(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 4.02 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile, 100 ml of toluene, 0.23 g of DL-proline and 3.32 g of 1,4-cyclohexanedione monoethylene ketal was heated and stirred for 3 hours under the reflux condition. After 20 ml of toluene was distilled off, the reaction mixture was cooled to room temperature. To the reaction mixture was added 100 ml of tetrahydrofuran. The mixture was cooled to 0° C. and then 1.01 g of sodium borohydride was added thereto. The mixture was stirred at room temperature for 6 hours and then cooled to 0° C. Thereto 100 ml of water and 100 ml of ethyl acetate were added. While the reaction mixture was stirred, 100 ml of an aqueous 1N hydrochloric acid solution was added dropwise, followed by extraction with 100 ml of ethyl acetate twice. An organic layer was washed with 100 ml of an aqueous saturated sodium hydrogen carbonate solution, 100 ml of an aqueous saturated sodium chloride solution and 100 ml of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.45 g of 2-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(3,3,3-trifluoropropylsulfonyl)acetonitrile (hereinafter referred to as the present compound (27)) represented by the following formula (27).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([O:16][CH3:17])[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C@H:11]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH3:17][O:16][C@H:15]1[C:14]([CH3:18])([CH3:19])[CH2:13][CH2:12][C@@H:11]([O:20][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1[C@H](COCc2ccccc2)[C@H](O)CCC1(C)C
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCO[C@@H]1CCC(C)(C)[C@H](OC)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of (1R,2R,3R)-2-(benzyloxymethyl)-3-methoxy-4,4-dimethylcyclohexanol (7 mg) and sodium hydride (5 mg, 60% dispersion in oil) and n-octyl bromide (20 ml) in dry N,N-dimethylformamide (0.3 ml) was stirred for 2 hrs at room temperature. The mixture was cooled to 0° C., and the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography (using n-hexane:ethyl acetate=10:1 as an eluent) gave benzyl [(1R,2R,6R)-2-methoxy-3,3-dimethyl-6-octyloxycyclohexyl]methyl ether (8 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].I[CH3:16]>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[N:7]2[CH3:16]
Reactant: O=C1CNc2c(F)cccc2N1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (415 mg, 2.5 mmol) in THF (10 ml) was added sodium hydride (60%, 100 mg, 2.5 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was cooled again in an ice/water bath and iodomethane (156 μl, 2.5 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred for 3 days. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and separated. The organic phase was washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 45:55) to give a white solid; yield 210 mg, 47%.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.[Cl-].[NH4+].CCOCC>O1CCCC1>[Br:16][C:10]1[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cccc2cc(-c3ccco3)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1cccc2c(Br)c(-c3ccco3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
7-Chloro-2-(2-furyl)-pyrazolo[1,5-a]pyridine (0.23 g, 1.05 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0° C. N-Bromosuccinimide (0.19 g, 1.05 mmol) was added. The reaction was stirred for 1 hour. The reaction solution was poured into equal volumes (10 mL) of saturated aqueous ammonium chloride and ether. The ether layer was collected and the solvent removed in vacuo to give the crude product The product was purified by silica gel chromatography (6:1 hexane:ethyl acetate) to give 0.3 g (96%) of 3-bromo-7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine as a solid. 1H NMR (CDCl3) δ 7.63 (d, 1H), 7.51 (d, 1H), 7.29 (d, 1H), 7.21 (dd, 1H), 6.98 (d, 1H), 6.58 (dd, 1H); MS m/z 298 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:41])[CH2:37][C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:38](=[O:39])[CH2:37][C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: COCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 95 (136 mg, 0.37 mmol) in dry DMF (7 ml) was added the acid 27 (300 mg, 3.0 eq, 1.1 mmol), HOBT (74 mg, 1.5 eq, 0.55 mmol) and EDC (210 mg, 3.0 eq, 1.1 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and sat NaHCO3 soln, the organic phase was collected, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was triturated with Et2O to afford title compound 92 (150 mg, 72% yield). 1H NMR (DMSO-d6) δ(ppm): 10.57 (s, 1H), 9.62 (s, 1H), 8.43 (d, J=5.48 Hz, 1H), 8.06 (m, 2H), 7.93 (m, 1H), 7.85 (m, 1H), 7.76 (s, 1H), 7.45 (m, 2H), 7.05 (m, 2H), 6.90 (m, 1H), 6.58 (m, 1H), 5.35 (s, 2H), 3.84 (m, 3H), 3.63 (s, 2H), 3.25 (s, 3H). MS (m/z): 562.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:24][CH:23]=[CH2:22])[C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
((R)-6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (3.26 g, 10 mmol) was dissolved in dimethylformamide (30 ml). Sodium hydride (50% in oil) (528 mg, 11 mmol) was added and stirred for 15 minutes at room temperature. Allyl bromide (0.95 ml, 11 mmol) was added and the reaction mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (400 ml) and extracted twice with 150 ml diethylether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (3.25 g). The crude product was purified with silica gel chromatography with cyclohexane/ethyl acetate (9:1) as eluent, yielding the purified product (2.7 g, 66%).