Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:14][C:15]([N-:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])#[N:13].NCCC(O)=O>C(O)C>[CH:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15](/[C:14](/[C:12]#[N:13])=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:16])=[CH:24][CH:23]=1
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: NCCC(=O)O
Solvent: CCO
Product: N#C/C(=C\c1ccc([N+](=O)[O-])cc1)C(=O)NCc1ccccc1
Yield: 73 %

Procedure:
0.45 g, 3 mM, p-nitro benzaldehyde, 0.61 g, 3.5 mM, N-(Cyano acetyl) benzyl amide (reference 9) and 50 mg β-alanine in 20 ml ethanol were refluxed for 5 hours. Cooling, and filtering gave 0.67 g, 73% yield, light yellow solid, mp-164°. NMR(CDCl3) δ 8.44 (1H,S,vinyl), 8.35, 8.07 (4H,AB, JAB=8.8 Hz), 7.35 (5H,m), 6.6(1H,br.t,NH), 4.63(2H,d,J=5.8 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccccc3F)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCc1ccccc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1ccccc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a reactor were charged 8.77 g (71 mmol) of 2-ethylphenol, 10.00 g (79 mmol) of benzyl chloride, 8.06 g (144 mmol) of KOH, and 30 g of DMF, and the mixture was stirred at 65° C. to 85° C. for 3 hours. To this mixture, 55 g of hydrochloric acid and 50 g of toluene were added, the organic layer was washed with water, and the solvent was evaporated. The residue was purified by column chromatography (n-hexane) to yield the desired product, 1-benzyloxy-2-ethylbenzene, as colorless liquid (9.23 g, Yield: 61%).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[C:48]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[C:47]([F:56])[C:46]([O:57][CH:58]([CH3:60])[CH3:59])=[C:45]([CH:61]=[O:62])[CH:44]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([C:43]2[C:48]([C:49]3[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=3)=[C:47]([F:56])[C:46]([O:57][CH:58]([CH3:60])[CH3:59])=[C:45]([CH:61]=[O:62])[CH:44]=2)[CH2:3][CH2:2]1
Reactant: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Cyclopropylboronic acid (13.8 g), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (6.58 g), tris(dibenzylideneacetone)dipalladium (0) (7.34 g) and 2M aqueous sodium carbonate solution (120 mL) were added to a solution of 6-bromo-2,4′-difluoro-3-isopropoxybiphenyl-4-carbaldehyde (28.5 g) in toluene (250 mL) at room temperature. The mixture was stirred at 100 C under argon atmosphere for 16 hours. The mixture was filtrated through celite. The filtrate was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (24.8 g).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[C:17]1([CH:23]2[CH2:25][O:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C)C>O1CCOCC1>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][C:2]([NH:1][CH2:25][CH:23]([OH:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15])(=[O:11])[NH2:12]
Reactant: c1ccc(C2CO2)cc1
Reactant: CC(C)(N)COc1ccc(O)c(C(N)=O)c1
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)NCC(O)c1ccccc1

Procedure:
A solution of 4.5 g of 5-(2-amino-2-methyl-propoxy)-salicylamide and 3.1 g of 2-phenyloxirane in 40 ml of dioxane is refluxed for 16 hours. The solvent is subsequently evaporated off under reduced pressure, and the residue is dissolved in 20 ml of 2N hydrochloric acid, and extracted with 50 ml of ether. The water phase is separated; it is rendered alkaline with concentrated ammonia, and the liberated base is extracted with 200 ml of ethyl acetate. Customary further processing yields a light-coloured foam, from which is obtained, by recrystallisation from isopropanol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1,1-dimethyl-ethyl]-aminomethyl]-benzyl alcohol, m.p. 121°-123°. It forms a neutral fumarate, m.p. 209°-210° (from methanol).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[NH:18][CH:17]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:18][CH:17]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (68.5 g, 601 mmol) was added dropwise at 0° C. to a solution of tert-butyl 1,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (13.5 g, 31.0 mmol) in CH2Cl2 (93 ml), and the mixture was stirred at this temperature for 15 min. After warming to RT, the reaction solution was stirred for a further 2.5 h. Subsequently, the reaction solution was adjusted to pH 7 to 8 using NaHCO3 solution, the organic phase was separated off, and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed by distillation. Workup was carried out by means of column chromatography to give 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one in a yield of 7.8 g (75% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:48])([S:44](F)(=[O:46])=[O:45])[C:40]([F:43])([F:42])[F:41]>CN(C)C=O>[F:38][C:39]([F:48])([S:44]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:46])=[O:45])[C:40]([F:43])([F:42])[F:41]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)F
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.0 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (23.5 mmol, 1.0 equivalent) in 100 mL of N,N-dimethylformamide was added 6.5 g of 325-mesh potassium carbonate (47 mmol, 2.0 equivalents). 1,1,2,2,2-pentafluoroethanesulfonyl fluoride (4 g, 20 mmol, 0.85 equivalents) was bubbled sub-surface into the reaction mixture over 3 hours, and the mixture was stirred for 0.5 hours. The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with 5 mL of N,N-dimethylformamide. The solution was diluted with 24 mL of water and 150 mL of ethyl acetate and the resultant solution was washed four times with 50 mL portions of 10 wt % aqueous sodium chloride, followed by 25 mL of saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, the drying agent was filtered off and the organic solution was concentrated in vacuo. The resultant solid was purified by chromatography over silica gel with gradient elution (40% ethyl acetate/hexanes to 60% ethyl acetate/hexanes). The desired product was dissolved in 10 mL of ethyl acetate and 200 mL of heptanes was added over 60 minutes. The product crystallized and was isolated by filtration. The wet cake was washed with 40 mL of heptanes and dried in vacuo with heating at 50° C. The title compound was isolated as a white solid (9.4 g, 67% yield). 1H NMR (600 MHz, CDCl3) δ ppm 8.60 (d, J=0.5 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.84 (dd, J=8.5, 1.7 Hz, 1H), 7.80 (d; J=2.5 Hz, 1H), 7.42 (dd, J=9.0, 2.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.27-7.26 (m, 2H), 5.82 (dd, J=8.0, 2.3 Hz, 1H), 3.30 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ ppm 162.6 (C), 157.5 (C), 149.8 (C), 147.1 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.23 (C), 132.18 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 61.0 (CH3), 35.8 (C), 30.8 (CH3). 19F NMR (564 MHz, CDCl3) δ ppm −79.1 (3F), −113.4 (2F). LC-MS m/z 599.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[N:12]O)[CH3:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCO.[ClH:23]>C1COCC1.CCOC(C)=O.CCOCC>[ClH:23].[ClH:23].[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]([NH2:12])[CH3:11]
Reactant: CC(=NO)c1cc2ccncc2[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: CC(N)c1cc2ccncc2[nH]1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a heterogeneous solution of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone oxime (Example 72) (0.31 g, 1.75 mmol) in THF (27.5 mL) was added lithium aluminum hydride (0.33 g, 8.79 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was refluxed for 1 h and then quenched by careful addition of hydrated Na2SO4. Ethyl acetate was added and the reaction mixture was stirred overnight. The solid was filtered off and thoroughly rinsed with EtOAc and EtOH. The filtrate was concentrated to give a yellow oil. The crude residue was dissolved in EtOAc and EtOH (100 mL; 1:1) and 2 M HCl in Et2O was added (1.85 mL). The precipitate was filtered off, rinsed with EtOAc and Et2O, and dried to provide 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethylamine dihydrochloride (0.29 g, 72%) as a light orange solid: mp 289-292° C.; 1H NMR (300 MHz, CD3OD) δ1.82 (3H, d, J=6.9 Hz), 4.88-4.95 (1H, m), 7.09 (1H, s), 8.17 (1H, d, J=6.4 Hz), 8.29 (1H, d, J=64 Hz), 9.13 (1H, s); ESI MS m/z 162 [C9H11N3+H]+; HPLC (Method A) 97.7% (AUC), tR=6.50 min.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCCO
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 3-dimethylamino-1-propanol (69 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 67 mg (0.28 mmol, 71%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 241 (M+1)+, calc. 241 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=1[O:13][CH3:14])[CH2:2][CH3:3].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>>[C:15]([C:8]1[CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]([O:13][CH3:14])=[C:6]([CH2:10][CH2:11][CH3:12])[CH:7]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CCCc1cccc(CCC)c1OC
Reactant: CCC(=O)Cl
Product: CCCc1cc(C(=O)CC)cc(CCC)c1OC

Procedure:
2,6-Di-n-propylanisole and propionyl chloride were treated in the same way as in step (a) of Example 30 to give 4-propionyl-2,6-di-n-propylanisole.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](Cl)([Cl:9])=[O:8]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:9][C:7]([O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: OC1CCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.543 g of cyclopentyl alcohol in 15 ml of methylene chloride is added to a 0° C. solution of 1.0 ml of a 10% toluene solution of phosgene in toluene in 10 ml of methylene chloride. The reaction is allowed to warm to room temperature and is stirred for 3 hours. The reaction is concentrated at reduced pressure, diluted with 15 ml of toluene and reconcentrated to dryness to give the product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][CH:8]=1.[CH:19]1([CH2:22][NH:23][C:24](=[O:42])[NH:25][C:26]2[CH:41]=[CH:40][C:29]([C:30]([N:32]([CH3:39])[CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[O:31])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:19]1([CH2:22][NH:23][C:24](=[O:42])[NH:25][C:26]2[CH:41]=[CH:40][C:29]([C:30]([N:32]([CH:33]3[CH2:34][CH2:35][N:36]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:4]=4)[CH2:37][CH2:38]3)[CH3:39])=[O:31])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCNCC1
Reactant: OC(c1cccc(CBr)c1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(Cc2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
2-(3-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (84 mg, 0.249 mmol) was added to a solution of 4-(3-(cyclopropylmethyl)ureido)-N-methyl-N-(piperidin-4-yl)benzamide (82 mg, 0.249 mmol), sodium iodide (15 mg, 0.100 mmol), and potassium carbonate (103 mg, 0.748 mmol) in acetonitrile (3 mL) and the solution was stirred at ambient temperature overnight. The reaction mixture was concentrated under vacuum, dissolved in dichloromethane, washed with water, and purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 3.5% methanol/96.5% dichloromethane) to afford the title compound (57 mg).
Reaction SMILES: S(Cl)(Cl)(=O)=O.C(S[S:9][CH2:10][CH3:11])C.[CH3:12][NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:12][N:13]([S:9][CH2:10][CH3:11])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]
Reactant: CCSSCC
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCSN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 30.3 %

Procedure:
A solution of 67 g of sulfuryl chloride in 100 ml of methylene chloride was added dropwise to a solution of 61 g of diethyldisulfide in 600 ml of methylene chloride cooled to -40° C. and after the temperature was raised to -5° C., the mixture was stirred for 5 minutes. The mixture was cooled to -40° C. and a solution of 57 g of N-methyl-N'-(3,4-dichlorophenyl)-urea in 460 ml of pyridine was added dropwise thereto. The mixture was stirred at -40° C. for 1 hour and for another hour at -20° C. The mixture was poured into an ice-water mixture and the pH was adjusted to 3.5 by addition of concentrated hydrochloric acid. The organic phase was decanted and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residue was crystallized from isopropyl ether and subjected to chromatography over silica gel. Elution with a 7-3 benzene-ethyl acetate mixture gave 22 g of N-methyl-N-ethylthio-N'-(3,4-dichlorophenyl)-urea melting at 71° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21])[CH3:18]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:14]1([C:12]([NH:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]([O:19][CH2:17][CH3:18])=[O:21])=[CH:3][CH:4]=3)[NH:8][N:7]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(Nc1n[nH]c2cc(Br)ccc12)C1CC1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(-c2ccc3c(NC(=O)C4CC4)n[nH]c3c2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a solution of N-(6-bromo-1H-indazol-3-yl)cyclopropanecarboxamide (560 mg, 2.0 mmol) in dioxane (20 mL) and 1N sodium carbonate solution (8 mL) were added 3-(ethoxycarbonyl)phenylboronic acid (388 mg, 2.0 mmol) and Pd(dppf)Cl2 (103 mg, 0.2 mmol). After the reaction was stirred at 100° C. for 4 hours and cooled to room temperature, the mixture was filtered through Celite and washed by ethyl acetate. The combined organic solution was washed by brine, dried with sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography with 20:1 (v/v) methylene chloride-methanol to afford the title product (560 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:2]=12.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>ClCCl>[N+:1]1([O-:22])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:2]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1CCc2cccnc21
Solvent: ClCCl
Product: COC(=O)C1CCc2ccc[n+]([O-])c21
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 1.53 g (8.47 mmol) of methyl 6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate from step A above in 30 mL of dichloromethane was added 1.61 g (9.31 mmol) of m-CPBA. The solution was allowed to stir for 1 h and then quenched with 50 mL of a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound as a light brown solid that was used without purification. LC-MS: m/z (E/S) 194.2 (MH)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20](O)=[O:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:23])[C:12]=2[C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(CC)CC.ClC(OC(C)C)=O.C1(C)C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:23])[C:12]=2[C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C(=O)O)nn23)CC1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (2.443 g, 5 mmol) and Et3N (0.836 ml, 6.00 mmol) in THF (100 mL) was added 1M isopropyl chloroformate/toluene (6.00 ml, 6.00 mmol) at 0° C. After 1 h, a solution of NaBH4 (0.567 g, 15.00 mmol) in cold water (20 mL) was added at once and stirred for at 0° C. LCMS after 1 h showed formation of desired product and presence of unreacted mixed unhydride intermediate. So, added additional NaBH4 (0.284 g, 7.5 mmol) and continued stirring for 3 h while allowing reaction mixture to slowly warm to 10° C. LCMS at this point showed still remaining about 10% unreacted material. So, added additional NaBH4 (0.189 g) and stirred for 1 h at 10° C. Then the reaction was quenched with AcOH (1 mL), diluted with Et2O (200 mL), washed with water (2×50 mL) and brine (25 mL). The organic layer dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (2.7 g, 5.12 mmol, 102% yield, 90% purity) as pale yellow paste which was used in next step without purification. LCMS (M+H)=475.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)(=[O:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:28])([F:29])[F:27])([C:22]([F:23])([F:24])[F:25])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:32])[CH3:31]
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1ccc(C2CC(C(O)(C(F)(F)F)C(F)(F)F)=NN2c2ccccc2Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
5-(4-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 4 of Preparation 17, 2-acetylphenylboronic acid (21.0 mg, 0.13 mmol), Pd(PPh3)4 (4.0 mg, cat.) and a 2N sodium carbonate solution (0.5 mL) were added to N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at 80° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 10.0 mg of the titled compound as a yellow liquid.