Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Na+].[I-].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:31])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1>CC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:31])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:15])[CH2:29][CH2:30]2)[CH:24]=1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(Cl)cc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
A mixture of 2-(3-bromopropyl)isoindoline-1,3-dione (2.68 g, 10 mmol) and NaI (20 mmol) in acetone was refluxed for 5 h, then to it was added 1-(5-chloro-2-methylphenyl)piperazine (2.11 g, 10.0 mmol). The reflux was continued for 12 h. Reaction was then cooled to room temperature, filtered through celite and concentrated. The crude product was recrystallized from acetone to give the title compound as a white solid (3.21 g, 81%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C1CCCCC1.ClC(Cl)(Cl)C(=N)O[C:19]([CH3:22])([CH3:21])[CH3:20].B(F)(F)F.CCOCC>ClCCl.CN(C)C=O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
At room temperature, to a solution of pyrrole-2-carboxylic acid (500 mg, 4,5 mmol) in anhydrous dichloromethane (5 mL) and anhydrous N,N-dimethylformamide (2.5 mL) was added anhydrous cyclohexane (20 mL). With vigorous stirring, to this clear solution was added (0.85 mL, 1.033 g, 4.73 mmol) of tert-butyl 2,2,2-trichloroacetimidate followed by dropwise addition of boron trifluoride diethyl etherate (170 mL). After stirring at room temperature for 2 hr, additional tert-butyl 2,2,2-trichloroacetimidate (0.85 mL, 1.033 g, 4.73 mmol) and boron trifluoride diethyl etherate (85 mL) were added to the reaction mixture. After stirring at room temperature for an additional 3 hr, additional tert-butyl 2,2,2-trichloroacetimidate (0.85 mL, 1.033 g, 4.73 mmol) and boron trifluoride diethyl etherate (85 mL) were added to the reaction mixture. After stirring at room temperature overnight, the reaction mixture was filtered through a pad of celite, and the residue was washed with ether. The solvent was removed from the filtrate by rotoevaportation and the crude product was purified by flash column chromatography on silica gel eluted with 3-6% ethyl acetate in hexane to give the title compound as a white solid (600 mg, 80% yield), homogeneous by TLC (1/1 hexane/Ethyl acetate).
Reaction SMILES: O.[NH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][C:5]=2[O:17][CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([O:21]C)=O.CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[C:23]1([CH:18]2[C:19](=[O:21])[NH:2][C:3]3=[C:16]4[C:11](=[N:10][C:9]5=[CH:8][CH:7]=[CH:6][C:5](=[C:4]35)[O:17]2)[CH2:12][CH2:13][CH2:14][CH2:15]4)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(Oc1cccc2nc3c(c(N)c12)CCCC3)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2c3c(nc4cccc(c24)OC1c1ccccc1)CCCC3
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Methyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]phenylacetate hydrate (5.26 g) was dissolved dry tetrahydrofuran (100 ml) and potassium tert-butoxide (1.70 g) was added. After stirring for 1 hr, saturated ammonium chloride solution (100 ml) was added, and stirring was continued for 30 min. The reaction mixture was evaporated and the solid was collected and washed with water. Recrystallization from dimethylformamide-water gave 3.69 g (77.0%) of product, mp 250° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=1[C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42]([NH:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=3)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: COc1cc(N)ncn1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1cc(NS(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)ncn1
Reaction time: 1 h
Yield: 5.6 %

Procedure:
To a vial containing 6-methoxypyrimidin-4-amine (0.063, 0.503 mmol) in 2Me-THF (1 ml) was added lithium bis(trimethylsilyl)amide (237 μl, 0.237 mmol) at −78° C. and stirred for 1 h. To this was then added a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (Intermediate LLL; 100 mg, 0.182 mmol) in 2Me-THF (1 ml) at −78° C. dropwise and stirred for 1 h. Reaction mixture was quenched with 3 drops of methanol and purified via reverse-phase chromatography with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(6-methoxypyrimidin-4-yl)isoquinoline-6-sulfonamide (0.005 g, 6%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (d, J=5.77 Hz, 1H) 8.63 (s, 1H) 8.52-8.56 (m, 1H) 7.82-7.89 (m, 2H) 7.77 (d, J=8.80 Hz, 1H) 7.50 (d, J=7.83 Hz, 1H) 7.41 (d, J=8.12 Hz, 1H) 7.28 (br. s., 2H) 3.96 (s, 3H) 3.75 (s, 3H); m/z (ESI) 491.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(C2CCCCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(C2CCCCC2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 74.4 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{[cyclohexyl(5-cyclohexyl-2-ethylthiophen-3-yl)methyl]amino}benzoic acid (233 mg) synthesized in Example 79 (3) and ethyl 3-(methylamino)propanoate (86.0 mg) to give the title compound (208 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)#[N:32].C(=O)(O)[O-].[Na+]>ClCCl>[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=2)=[O:38])=[CH:35][CH:34]=1)#[N:32]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C#N)cc3)cc2)c2ccccc12
Yield: 48.5 %

Procedure:
Ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (176 mg, 0.569 mmol) and triethylamine (173 mg, 1.71 mmol) were dissolved in dichloromethane (15 mL), and in an ice bath dichloromethane solution (10 mL) of 4-cyanobenzoyl chloride (95 mg, 0.574 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 121 mg, at a yield of 48.5%.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1.[H][H]>CO.[C].[Pd]>[ClH:1].[OH:2][CH:3]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:35])[CH:22]=1)[CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:9][CH2:10]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccc(O)c(O)c2)CC1
Yield: 95 %

Procedure:
2.31 g of 1-[2-hydroxy-2-(3,4-dibenzyloxyphenyl)-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine hydrochloride is dissolved in 250 ml of methanol. 0.3 g of palladium carbon (10%) is added thereto, and the mixture is vigorously shaked in a hydrogen stream under atmospheric pressure. After discontinuation of the absorption of hydrogen, the catalyst is filtered off, and the mother liquor is concentrated. To the residual syrup is added ethyl acetate, and the mixture is well stirred. The mixture is filtered to obtain powdered product, and the product is washed with ethyl acetate and dried to obtain 1.52 g of 1-[2-hydroxy-2- (3,4-dihydroxyphenyl)-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine hydrochloride as amorphous powder. When subjected to thin layer chromatography using a lower layer of a mixture of chloroform/methanol/acetic acid/water (10/10/1/10), this product provides single spot at Rf =0.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH2:13])[CH2:7]1.[C:18]1([C:24]2[O:25][C:26]([CH3:33])=[C:27]([CH2:29][C:30](O)=[O:31])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:30](=[O:31])[CH2:29][C:27]2[N:28]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:25][C:26]=2[CH3:33])[CH2:7]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 48.5 %

Procedure:
Example 54 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 9 (0.055 g) and 2-phenyl-5-methyl-4-oxazolylacetic acid (0.050 g) to give the title compound (0.046 g).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Br:16])=[CH:14][C:5]2[C:6]([C:9]([O:11]CC)=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1.O[Li].O.Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:15]([Br:16])=[CH:14][C:5]2[C:6]([C:9]([OH:11])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1coc2cc(N)c(Br)cc12
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc2occ(C(=O)O)c2cc1Br
Yield: 97.6 %

Procedure:
To a solution of the compound ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58 g, 204 mmol) in 1,4-dioxane and H2O (850 mL and 150 mL) was added LiOH.H2O (42.8 g, 1.02 mol). The reaction mixture was refluxed for 2 hours, and then 400 mL H2O was added to the reaction mixture. After acidifying to pH 4˜5 with HCl, the resulting solid was filtered to give 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, yield: 97%). 1H-NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.02 (s, 1H), 5.51 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]Cl>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[CH:3][C:4]=2[C:26]([F:29])([F:27])[F:28])[CH:8]=[CH:9]3)/[S:21][C:20]1=[O:22]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-3-[3-(Dimethylamino)propyl]-5-[(1-{[4-fluoro-2-(trifluoromethyl)phenyl]-methyl}-1H-indol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 249) and 3-(dimethylamino)propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH3:26])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1.[CH2:29](N=C=O)C.CN=C=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH2:26][CH3:29])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1
Reactant: CCN=C=O
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: CN=C=O
Product: CCNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 79 was prepared in the manner of compound 24 substituting ethylisocyanate for methyl isocyanate and refluxing for 16 h [MS 408 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:13](=[O:15])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.7 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (100 mg, 0.30 mmol) in methylene chloride (8 mL) was cooled to 0° C. To this solution was then added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 180 μL, 0.36 mmol) and N,N-dimethylfomamide (two drops) which produced gas evolution and it was then stirred at 0° C. for 20 minutes and 40 min at 25° C. After this time, the reaction was concentrated in vacuo and azeotroped with methylene chloride (10 ml). In a separate flask a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 80 mg, 0.33 mmol), 2,6-lutidine (52 μL, 0.45 mmol) in methylene chloride (6 mL) was cooled to 0° C. in an ice bath. To this solution was then dropwise the solution of the prepared acid chloride diluted with another portion of methylene chloride (6 mL). After addition was complete, the reaction was stirred at 0° C. for 15 min and at 25° C. for 3 hours. After this time it was concentrated in vacuo and purified on an AnaLogix Intelliflash system (40 g column, 30% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) to afford N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionamide (138 mg, 86%) as a clear colorless oil: 1H NMR (300 MHz, DMSO-d6) δ ppm −0.09-0.06 (2×s, 6H, 2×SiCH3), 0.77, 0.82 (2×s, 9H, 3×CH3), 1.44-1.57 (m, 1H, CH of CH2), 1.70-2.22 (m, 4H, CH and 3×CH of 2×CH2), 3.22-3.29 (m, 1H, OCH of OCH2), 3.33, 3.34 (2×s, 3H, SO2CH3), 3.51-3.63 (m, 1H, OCH of OCH2), 3.66-3.94 (m, 5H, ArCH, SiOCH2, and 2×OCH of 2×OCH2), 4.01-4.08 (m, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.60 (2×dd, Jo=8.2 Hz, Jm=1.6 Hz, 1H, Ar), 7.71 (2×d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.82, 10.83 (2×s, 1H, NH).
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=[CH:23][C:24](OCC)=O)[CH2:19][CH2:18]2)[CH:9]=1.C(CP(=O)(OCC)OCC)#[N:40]>>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:38])([CH3:37])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH2:19][C:20](=[CH:23][C:24]#[N:40])[CH2:21][CH2:22]2)[CH:9]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=CC#N)CC2)nc2ccnn12

Procedure:
2-(4-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate, but with diethyl cyanomethylphosphonate substituted for triethyl phosphonoacetate.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O>Br>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccccc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](Cc3ccccc3F)C2)o[nH]1
Yield: 69.4 %

Procedure:
(2S,4S)-Methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (199 mg, 0.60 mmol) was stirred in hydrogen bromide (33% in AcOH) overnight (17 h). Evaporation of solvents and purification by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) yielded 5-((2S,4S)-2-(2-fluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (115 mg, 70%). 1H NMR (600 MHz, DMSO) δ 1.47-1.56 (m, 1H), 1.67-1.81 (m, 3H), 2.57-2.64 (m, 1H), 2.72 (d, 2H), 2.81-2.87 (m, 1H), 2.87-2.95 (m, 1H), 3.12-3.18 (m, 1H), 5.70 (s, 1H), 7.09-7.18 (m, 2H), 7.22-7.33 (m, 2H). HRMS Calcd for [C15H17FN2O2+H]+: 277.1352. Found: 277.1352.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH2:12][C:13]([O:15]CCCC)=[O:14])([CH3:10])([CH3:9])[CH3:8]>CO.O>[C:7]([O:11][CH2:12][C:13]([OH:15])=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCCOC(=O)COC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OCC(=O)O
Temperature: 0 °C

Procedure:
To 100 ml of a 50:50 (v/v) methanol/water solution containing 14.35 g of potassium carbonate, was added n-butyl 2-tert-butoxyacetate (6.50 g, 0.0346 mol). The mixture was heated at reflux for 17 hours and the volatiles removed on a flash evaporator. The remaining solution was cooled to approximately 0° C. and acidified to pH 3-4 with cold 50% aqueous hydrogen chloride. The product was extracted with ether, the ether extract washed with brine and dried over magnesium sulfate, then concentrated in vacuo to give the title compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][CH2:12][Cl:13].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[Cl:13][CH2:12][CH2:11][CH2:10][C:9]1[C:3]2[C:2](=[CH:7][C:6]([F:8])=[CH:5][CH:4]=2)[NH:1][N:15]=1
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Fc1ccc2c(CCCCl)n[nH]c2c1
Temperature: -3 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a suspension of 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (500 mg, 2.3 mmol) in conc. HCl (3.2 mL) was added a solution of NaNO2 in H2O (0.7 mL) and stirred for 1 h at −6-0° C. A solution of SnCl2.2H2O (1.25 g, 5.51 mmol) in conc. HCl (1.7 mL) was added the reaction mixture and stirred for additional 1 h at 0° C. The reaction was quenched by addition of ice water and extracted with Et2O. The combined organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give a white solid. It was recrystallized to give pure 3-(3-chloropropyl)-6-fluoroindazole (420 mg, 86%).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([OH:29])[CH2:27][OH:28])=[CH:20][CH:19]=2)[C:13]([C:30]#[N:31])=[C:12]([S:32][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[O:37][CH:38]=2)[N:11]=1.[ClH:46]>C(#N)C.[Cu](Cl)Cl>[Cl:46][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([OH:29])[CH2:27][OH:28])=[CH:20][CH:19]=2)[C:13]([C:30]#[N:31])=[C:12]([S:32][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)[O:37][CH:38]=2)[N:11]=1
Reactant: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
171 mg (1.46 mmol) of isopentyl nitrite and 196 mg (1.46 mmol) of copper(II) chloride were initially charged in 18 ml of acetonitrile. 389 mg (0.73 mmol) of the compound from Example 40A were added, and the mixture was then stirred at 60° C. for 3 h. After cooling to RT, 20 ml of 1N hydrochloric acid were added. The aqueous phase was extracted twice with in each case 30 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed, and the product was then used without further purification for the subsequent reaction.
Reaction SMILES: [C:1]12([CH2:11]OC3C(Cl)=CC(C(OC)=O)=CN=3)CC3CC(CC(C3)[CH2:2]1)C2.Cl[C:25]1[C:26]([O:36][CH2:37][C:38]23[CH2:48][C:42]4([F:49])[CH2:43][C:44]([F:47])([CH2:46][C:40]([F:50])([CH2:41]4)[CH2:39]2)[CH2:45]3)=[CH:27][C:28]([F:35])=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>>[CH:11]1([C:25]2[C:26]([O:36][CH2:37][C:38]34[CH2:45][C:44]5([F:47])[CH2:43][C:42]([F:49])([CH2:41][C:40]([F:50])([CH2:46]5)[CH2:39]3)[CH2:48]4)=[CH:27][C:28]([F:35])=[C:29]([CH:34]=2)[C:30]([O:32][CH3:33])=[O:31])[CH2:1][CH2:2]1
Reactant: COC(=O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Reactant: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Product: COC(=O)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Yield: 62 %

Procedure:
Following the procedure as described in Example 150 step 3 and making variations as required to replace methyl 6-(adamantan-1-ylmethoxy)-5-chloronicotinate with methyl 5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoate. Purification by silica gel column chromatography (10:1 hexanes:ethyl acetate) gave the title compound as a colorless solid (0.57 g, 62%): 1H NMR (300 MHz, CDCl3) 7.49 (d, J=8.2 Hz, 1H), 6.51 (d, J=12.6 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 2H), 2.24-2.14 (m, 3H), 2.14-2.04 (m, 3H), 1.99-1.88 (m, 1H), 1.86-1.79 (m, 6H), 0.96-0.88 (m, 2H), 0.66-0.58 (m, 2H); MS (ES+) m/z 413.2 (M+1).