Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].Cl>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14](=[O:15])[NH:13][CH:10]([CH3:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: CC(C)N=C=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1ccc(Cl)cc1F
Temperature: 60 °C
Yield: 91.4 %

Procedure:
To 5 g (34 mmol) 4-Chloro-2-fluorophenol and 416 mg (3.41 mmol) 4-dimethylaminopyridine in 18 ml THF are added 3.7 ml (37.5 mmol) isopropyl isocyanate and the mixture is heated for 20 hours at 60° C. After cooling down to room temperature 2 M HCl is added and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to yield 7.2 g isopropylcarbamic acid 4-chloro-2-fluorophenyl ester as the crude product. To 7.2 g (31 mmol) isopropylcarbamic acid 4-chloro-2-fluorophenyl ester and 5.1 ml tetramethylene diamine in 300 ml diethyl ether are added 5.9 ml (32.5 mmol) (trimethylsilyl)(trifluoromethan)sulfonate at room temperature. After 30 minutes the mixture is cooled to −70° C., 10.2 ml tetramethylene diamine and 27 ml of a 2.5 M n-BuLi solution are added successively. After one hour at −70° 24 ml DMF in are added at −70° C. and the mixture is stirred another hour at −70° C. 130 ml ethanol and 36 ml of a 2 M aqueous NaOH are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is set acidic by addition of 100 ml 2 M aqueous HCl and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The crude product is purified by chromatography on silica gel to yield 1.1 g 5-chloro-3-fluoro-2-hydroxybenzaldehyde. 1.1 g (6.1 mmol) 5-chloro-3-fluoro-2-hydroxybenzaldehyde and 1.56 g (11.3 mmol) potassium carbonate are stirred vigorously in 11 ml DMF while 0.7 ml methyliodide are added. Stirring is continued for 18 hours and water is added. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 10%) to yield 570 mg 5-chloro-3-fluoro-2-methoxybenzaldehyde. 1H-NMR (CDCl3); δ=4.10 (d, 3H), 7.35 (dd, 1H), 7.59 (m, 1H), 10.35 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[N:42][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+].C>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:37][C:38]1[CH:39]=[C:40]([C:2]2[CH:3]=[C:4]3[C:17]4([CH2:21][O:20][C:19]([NH2:22])=[N:18]4)[C:13]4([CH2:14][O:15][CH2:16]4)[C:9]4([CH2:12][CH2:11][CH2:10]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:41]=[N:42][CH:43]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C2(CCC2)O3)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (300 mg, 0.531 mmol), 5-methylpyridine-3-boronic acid (145 mg, 1.06 mmol), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) and Na2CO3 (169 mg, 1.59 mmol) in dioxane-H2O (4:1, 6.0 mL) was stirred for 1 hour at 100° C. To the mixture was added charcoal and the mixture was stirred for 10 minutes at 50° C. The mixture was filtered through celite pad (eluted with EtOAc) and the filtrate was washed with H2O and brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. To the residue were added toluene (3.0 mL) and silica gel (neutral; 900 mg), and the mixture was stirred for 3 hours at 120° C. After concentration of the reaction mixture at reduced pressure, the residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) to afford 6′-(5-methylpyridin-3-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (151 mg).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.BrC1C=CC(O[C@@H]2CCC[C@@H]2N)=CC=1[F:35]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:19][C:20]=1[F:35]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Reactant: N[C@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1S,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentanamine was used instead of cis-2-(4-bromophenoxy)cyclopentanamine, and the chromatographic purification was carried out with a gradient of 0% to 10% methanol in dichloromethane, to provide the title compound as an off-white solid. Yield: 4.15 g, 10.9 mmol, 54% from (1R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate (5 steps). 1H NMR (500 MHz, CDCl3) δ 1.36 (d, J=6.7 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.62-1.69 (m, 1H), 1.77-1.90 (m, 3H), 1.92-2.00 (m, 1H), 2.10-2.15 (m, 1H), 3.14 (septet, J=6.8 Hz, 1H), 3.86 (m, 1H), 4.56-4.60 (m, 2H), 6.61 (ddd, J=8.9, 2.8, 1.1 Hz, 1H), 6.70 (dd, J=10.3, 2.8 Hz, 1H), 7.43 (dd, J=8.8, 8.1 Hz, 1H). The absolute configuration of N-[(1S,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl]propane-2-sulfonamide was assigned by analogy to the stereochemistry of compounds in Example 7 and Preparation 6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13]C(OC(C)(C)C)=O)=[C:8]([F:21])[CH:7]=1>C(O)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[C:8]([F:21])[CH:7]=1
Reactant: COC(=O)COc1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Solvent: O=CO
Product: COC(=O)COc1ccc(CN)c(F)c1
Temperature: 60 °C
Yield: 87.6 %

Procedure:
[4-(tert-Butoxycarbonylamino-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester (0.94 g, 3.0 mmol) was dissolved in formic acid (13 mL) and heated to 60° C. When the reaction was complete, the formic acid was removed under reduced pressure, and co-evaporated with chloroform and ethanol (1:1) to remove any excess formic acid. The resulting formate salt was taken up in ethyl acetate and shaken with saturated sodium bicarbonate. The organic layer was dried (Na2SO4) concentrated in vacuo to provide 0.56 g of product which was used directly in the next step.
Reaction SMILES: Br.[CH:2]1([C:5]2[CH:6]=[CH:7][C:8](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=3)=[CH:14]/[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[N:9][C:10]=2[O:11]C)[CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([C:5]2[C:10](=[O:11])[NH:9][C:8](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=3)=[CH:14]/[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:6]=2)[CH2:3][CH2:4]1
Reactant: COc1nc(/C(=C/CCNC(C)=O)c2ccc(SC)cc2)ccc1C1CC1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(/C(=C\CCNC(C)=O)c2ccc(C3CC3)c(=O)[nH]2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of N-{(3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-yl}acetamide (87 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 80° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of chloroform-ethyl acetate-hexane. Filtration gave the title compound as a colorless solid (54 mg, 64%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:5])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: Nc1ccc(Cn2ccnc2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(Cn4ccnc4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step 120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 519.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.40 (DCM/MeOH, 9:1).
Reaction SMILES: CSC.C([O:11][C@H:12]1[C@@H:17]([O:18]CC2C=CC=CC=2)[C@@H:16]([O:26]CC2C=CC=CC=2)[C@@H:15]([CH2:34][O:35]CC2C=CC=CC=2)[O:14][CH:13]1[C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[C:45]([CH2:53][C:54]2[S:58][C:57]3[CH:59]=[CH:60][C:61]([F:63])=[CH:62][C:56]=3[CH:55]=2)[CH:44]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:63][C:61]1[CH:60]=[CH:59][C:57]2[S:58][C:54]([CH2:53][C:45]3[CH:44]=[C:43]([C@H:13]4[C@H:12]([OH:11])[C@@H:17]([OH:18])[C@H:16]([OH:26])[C@@H:15]([CH2:34][OH:35])[O:14]4)[C:52]4[C:47]([CH:46]=3)=[CH:48][CH:49]=[CH:50][CH:51]=4)=[CH:55][C:56]=2[CH:62]=1
Reactant: Fc1ccc2sc(Cc3cc(C4O[C@H](COCc5ccccc5)[C@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Product: OC[C@H]1O[C@@H](c2cc(Cc3cc4cc(F)ccc4s3)cc3ccccc23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 45.3 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfide (1.72 ml) and a boron trifluoride-diethyl ether complex (0.86 ml, 6.8 mmol) were added to a solution of (3R,4R,5S,6R)-3,4,5-trisbenzyloxy-6-benzyloxymethyl-2-[3-(5-fluorobenzo[b]-thiophen-2-ylmethyl)naphthalen-1-yl]tetrahydropyran (550 mg, 0.68 mmol) in methylene chloride (15 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 2.5 days, then a saturated sodium hydrogen carbonate aqueous solution was added under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried with sodium sulfate, and thereafter the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (40:1)] to obtain the title compound (140 mg, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[F:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[C:19]([F:21])[CH:20]=1>C(N(CC)CC)C>[F:21][C:19]1[CH:18]=[C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:16]=[C:15]([F:14])[CH:20]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3cc(F)cc(F)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 4-(3,5-difluorophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(3,5 -difluorophenyl)-4-(p-nitrobenzyl)piperazine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[C:25]([S-:27])#[N:26].[K+].BrBr>C(O)(=O)C>[NH2:26][C:25]1[S:27][C:7]2[CH:6]=[C:5]([CH:8]([OH:24])[CH:9]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13][CH2:12]3)[CH3:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C(O)c1ccc(N)cc1)N1CCC(Cc2ccccc2)CC1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C(O)c1ccc2nc(N)sc2c1)N1CCC(Cc2ccccc2)CC1
Reaction time: 5 h
Yield: 46.8 %

Procedure:
To a stirred solution of 4 g of 1-p-aminophenyl-2-(4-benzyl-piperidin-1-yl)-propan-1-ol and 4.6 g of KSCN in 35 ml of glacial acetic acid was added dropwise 3.8 g of Br2 in 10 ml of glacial acetic acid. After 5 hours, the yellow suspension was filtered and the solution was poured into 100 ml of a concentrated hydroxide ammonium solution. After extraction with ethylacetate, the organic phase was washed with brine and dried. The solvent was removed and the residue was filtered on a small of silica gel eluting with acetone/cyclohexane ¼, affording 2.2 g of the title compound, m.p. 197-200° C., [α]20D=−15.6±0.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[C:9](=O)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1OCCN(Cc1ccccc1)C(=O)CCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1OCCN(CCCc1c[nH]c2ccccc12)Cc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-propion-amide in tetrahydrofuran (50 mL) at room temperature was added lithium aluminum hydride (1.8 g). The reaction was heated to reflux for 12 hours then allowed to cool to room temperature. The reaction was quenched with saturated ammonium chloride and the solid precipitates filtered through celite. The solvent was concentrated under vacuum and the product purified by chromatography (5% methanol-methylene chloride) to afford 2.0 g (86%) of product as a yellow oil. MS EI m/e 414 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:19]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:27]([N:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:10])=[O:9])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Br)N(Cc1ccccc1)Cc1ccccc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 88.5 %

Procedure:
2-Bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol) and triethylamine (455 mg, 0.63 mL, 4.5 mmol) were dissolved in THF (15 mL), and the mixture was cooled to 10° C. Dibenzylamine (849 mg, 0.83 mL, 4.3 mmol) was then added dropwise. The cooling bath was removed, and the reaction mixture was stirred for 10 h at rt and then an additional 6 h at 60° C. After cooling to rt, the solvent was removed under reduced pressure, and ethyl acetate was added. The organic layer was successively washed with 1N HCl, water, semi-saturated aq Na2CO3 solution, water, and brine. After drying with Na2SO4 and filtration, the solvent was removed under reduced pressure to afford the title compound as off-white crystals (1.44 g, 88%). 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 4H), 7.08 (m, 4H), 7.27 (m, 6H), 7.41 (m, 2H), 7.78 (d, 1H), 8.19 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]1=[O:12].C(O)C.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>CN(C=O)C>[OH:11][C:4]1[C:3](=[O:12])[N:2]([CH3:1])[C:10]2[C:5]([C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CN1C(=O)C(=O)c2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.9 %

Procedure:
1-Methylindoline-2,3-dione (5.0 g, 31.0 mmol) was stirred in DMF (15 mL) and Ethanol (85 mL) at 0° C. Ethyl 2-diazoacetate (4.51 mL, 43.4 mmol) was added. The ice bath was removed and the mixture was stirred at rt for two days. The mixture was evaporated to remove most of the EtOH. 1N HCl (ca. 100 mL) was added. It was stirred at rt for 3 h. LC-MS showed the desired ring expansion product. The precipitate was filtered and rinsed with H2O (2×) and dried under vacuum to give Intermediate 16 (5.05 g, 20.42 mmol, 94% yield) as slightly tan solids. LC-MS (ESI) 248.0 (M+H), RT=2.91 min (Method A).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:30])=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH3:30])=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Product: COC(=O)C(Oc1ccc(Oc2ccccc2)cc1)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 35, 4.66 g of p-phenoxyphenol is reacted with methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.02 mole) in refluxing methanol-benzene for 24 hrs to give the product as a viscous oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.[CH3:28][O:29][C:30]([C:32]1[CH:36]=[C:35]([NH2:37])[NH:34][N:33]=1)=[O:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]([C:32]1[CH:36]=[C:35]2[NH:37][C:5]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:11][CH:12]=3)=[C:4]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:3](=[O:2])[N:34]2[N:33]=1)=[O:31]
Reactant: COC(=O)c1cc(N)[nH]n1
Reactant: COC(=O)C(C(=O)c1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Yield: 16.1 %

Procedure:
A mixture of 274 mg (0.747 mmol) of 3-(4-benzyloxy-phenyl)-2-cyclohexyl-3-oxo-propionic acid methyl ester, 106 mg (0.747 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 15 mg (10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 10 mL of toluene was heated at reflux for 88 h. The reaction mixture was then concentrated to a residue which was chromatographed on silica gel (Biotage; gradient elution 2% to 20% ethyl acetate in dichloromethane) to afford 55 mg (16% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by 1H NMR; LC-MS—calcd for C27H27N3O4 [M++H]+: 458.2, found: 458.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:20][CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: CN(C)CCN
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: CN(C)CCNCC(=O)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.68 cm3 of N,N-dimethylethylenediamine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (95/5/1 by volume). The fractions containing the expected product are combined, concentrated under reduced pressure and then dried (90 Pa; 45° C.) to give 113 mg of N-(6-chloro-1H-indazol-3-yl)-2-[[2-(dimethylamino)ethyl]amino]acetamide in the form of a white solid melting at 104° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:46][CH2:47][CH:48]([OH:60])[CH2:49][N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1>C(Cl)Cl>[CH2:51]1[C:52]2[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:58][CH2:59][N:50]1[CH2:49][CH:48]([OH:60])[CH2:47][NH:46][C:12]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (2.5 g, 10.5 mmol) in DCM (25 mL) was added EDCI (3.0 g, 15.7 mmol), HOBt (2.1 g, 15.7 mmol), Et3N (2.1 g, 21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (2.2 g, 10.5 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (3.2 g, 71%). LCMS (m/z): 426.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([C:15]1[N:19]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1)[CH3:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([C:15]1[N:19]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:24][CH2:25]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1)[CH3:14]
Reactant: CCc1nc2ccccc2n1C1CCNCC1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2ccccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.5 g) and 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.5 g) in DMF (5 ml) was added K2CO3 (1.0 g) and KI (0.05 g). The mixture was heated at 100° C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 0.6 g of the title compound as colourless crystals. Mp. 182-184° C.