Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.FC(F)(F)COP([CH2:31][C:32]([O:34][CH3:35])=[O:33])(OCC(F)(F)F)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:48](=O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCCC1.C1(C)C=CC=CC=1>[C:49]1(/[CH:48]=[CH:31]\[C:32]([O:34][CH3:35])=[O:33])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccccc1
Temperature: -78 °C

Procedure:
9.4 g of 18-crown-6 and 1.7 ml of methyl [bis(2,2,2-trifluoroethoxy)-phosphoryl]acetate are dissolved under argon in 120 ml of dry tetrahydro-furan and cooled to −78° C. 14.3 ml of a 0.5 molar solution of potassium bis(trimethylsilyl)amide in toluene are added to this mixture, followed by 0.85 ml of benzaldehyde. After stirring at −78° C. for thirty minutes, the reaction mixture is quenched by adding saturated ammonium chloride solution and extracted with five portions each of 50 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then the solvent is removed in vacuo. The residue is purified on silica gel with n-heptane:ethyl acetate=20:1 as eluent. 1.1 g of methyl (Z)-3-phenylacrylate are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]2[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:20]3[C:15](=[CH:16][N:17]=[C:18]4[NH:28][CH:27]=[CH:26][C:19]4=3)[CH:14]=2)=[CH:11][C:10]([O:29][CH3:30])=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH2:31]([O:33][C:34](=[O:37])[CH2:35]Cl)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][N:28]1[C:18]2=[N:17][CH:16]=[C:15]3[C:20]([N:21]([CH2:24][CH3:25])[C:22](=[O:23])[C:13]([C:12]4[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=[C:3]([C:4](=[O:5])[NH:6][CH2:7][CH3:8])[C:2]=4[Cl:1])=[CH:14]3)=[C:19]2[CH:26]=[CH:27]1)[CH3:32]
Reactant: CCOC(=O)CCl
Reactant: CCNC(=O)c1cc(OC)cc(-c2cc3cnc4[nH]ccc4c3n(CC)c2=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCNC(=O)c1cc(OC)cc(-c2cc3cnc4c(ccn4CC(=O)OCC)c3n(CC)c2=O)c1Cl
Temperature: 60 °C

Procedure:
A mixture of 2-chloro-N-ethyl-3-(9-ethyl-8-oxo-8,9-dihydro-3H-3,4,9-triaza-cyclopenta[a]naphthalen-7-yl)-5-methoxy-benzamide (7.6 mg, 0.018 mmol), chloro-acetic acid ethyl ester (2.2 mg, 0.018 mmol), potassium carbonate (0.89 mg, 0.0064 mmol) and acetone (0.5 mL) is heated up to 60° C. for 2 h. Solvent is removed and water is added. The mixture is extracted with chloroform and methanol (20:1) and the extracts is combined and dried with MgSO4. After removal of the solvent, the residue is purified on silica gel column (ethyl acetate:hexane=4:1) to give desired product. MS m/z 511.1 (M+1). 2.5 mg of the product is hydrolyzed with LiOH.H2O in THF, MeOH and H2O at rt for 1 h to give the desired acid product. MS m/z 483.1 (M+1).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:35](=[O:36])[O:37][CH:38]([CH3:40])[CH3:39])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
80.0 mg (0.217 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in 1 ml of dichloromethane. 75.9 mg (0.750 mmol) of triethylamine was added to the obtained solution. Then a solution of 31.9 mg (0.260 mmol) of isopropyl chloroformate in 0.5 ml of dichloromethane was slowly added to the obtained mixture. After stirring for 30 minutes, the obtained product was purified by the silica gel chromatography (hexane:ethyl acetate=93:7 to 3:1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.O=S(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:19])([F:18])[F:1])=[CH:5][CH:6]=2)=[N:15][CH:14]=1
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2ccc(CCl)cn2)cc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
[6-(4-Trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol (0.40 g, 1.49 mmol) was dissolved in CH2Cl2 (7.2 ml) and treated dropwise at 0° C. with SOCl2 (0.22 ml, 2 eq.). The reaction mixture was kept at 0° C. for 5 min and at RT for 30 min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents produced 0.419 g (1.46 mmol, 98%) of the title compound as off-white solid of mp. 34–36° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6]C(=O)[O:8][C:9](=O)[C:4]=2[CH:3]=1.[NH4+:14].[OH-]>>[NH2:6][C:5]1[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=1[C:9]([NH2:14])=[O:8]
Reactant: [NH4+]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: [OH-]
Product: NC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Bromo-1H-benzo[d][1,3]oxazine-2,4-dione (56.0 g, 230 mmol) was suspended in 1 N aq. NH4OH (600 mL, 2.6 equivalents), and the suspension was stirred 3 d at room temperature. After filtration, the collected solid was washed with water and subsequently dissolved in tetrahydrofuran. This solution was filtered, evaporated to dryness, and dried by repeated azeotropic distillation with toluene. The solid was suspended in CH2Cl2, filtered, and washed once with CH2Cl2 yielding 35.4 g (71.2%) of 2-amino-5-bromo-benzamide.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.6 g) containing N,N-dimethyl-L-valinamide hydrochloride obtained in B) and triethylamine (44.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (14.4 g) at room temperature, and the reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (4.2 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>CN(C=O)C.O1CCCC1>[CH3:27][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[N:4]1)(=[O:24])=[O:25]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2nc(C(=O)O)c3ccccc32)c(C)c1
Temperature: 0 °C

Procedure:
NaH (60% in oil, 40 mmol) is washed under argon with petroleum ether and then suspended in 60 ml of anhydrous DMF. An indazole-3-carboxylic acid solution (3.35 g, 20 mmol) in anhydrous DMF (50 ml) is added dropwise to this suspension kept at 0° C. The reaction mixture becomes clear. When the addition is complete, the medium is allowed to react for 30 min at room temperature and then the reaction mixture is again cooled to 0° C. Mesitylenesulphonyl chloride (4.82 g, 22 mmol) in solution in anhydrous tetrahydrofuran (THF) (50 ml) is added. The ice bath is removed and a suspension appears. The medium is allowed to react for 30 min at room temperature. The solvents are evaporated under vacuum and the residue is taken up in 0.1N NaOH solution. The solution obtained is washed with diethyl ether and then acidified with 6N HCl. The compound which separates is filtered, and taken up in AcOEt. The AcOEt solution is dried over Na2SO4 and then evaporated. The residue (6.18 g) is recrystallized from AcOEt/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a suspension containing 3.0 g (15 mmol) of 2-chloro-6-nitrobenzoic acid in 150 ml of dichloromethane was added 2.8 g (22 mmol) of oxalyl chloride followed by 0.055 ml (0.75 mmol) of N,N-dimethylformamide. The reaction was allowed to stir at room temperature for 2 h, quenched with 50 ml of methanol and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 10% ethyl acetate/hexanes gave 3.1 g (9-7%) of product.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: CC(C)c1ccc2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc2c(Cl)ncnc2c1
Yield: 97 %

Procedure:
The product of Example 91E (100 mg, 0.5313 mmol) in phosphorous oxychloride (2 mL) was heated under a nitrogen atmosphere at reflux for one hour. The reaction was cooled and concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (50 mL) and washed sequentially with saturated aqueous sodium hydrogencarbonate (2×25 mL), water (25 mL), and brine (25 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as a yellow oil (107 mg, 0.5177 mmol, 97%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.99 Hz, 6 H) 3.14-3.29 (m, 1 H) 7.86 (dd, J=8.64, 1.65 Hz, 1 H) 7.93 (s, 1 H) 8.22 (d, J=8.46 Hz, 1 H) 9.07 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:7][S:8]([C:11]1[CH:12]=[N:13][C:14](Cl)=[C:15]([Br:17])[CH:16]=1)(=[O:10])=[O:9])([CH2:5][OH:6])[CH3:4].[CH3:19][O-:20].[Na+].Cl>CO>[OH:1][CH2:2][C:3]([NH:7][S:8]([C:11]1[CH:12]=[N:13][C:14]([O:20][CH3:19])=[C:15]([Br:17])[CH:16]=1)(=[O:10])=[O:9])([CH2:5][OH:6])[CH3:4]
Reactant: C[O-]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncc(S(=O)(=O)NC(C)(CO)CO)cc1Br
Yield: 39.4 %

Procedure:
To a solution of 5-Bromo-6-chloro-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (550 mg, 2 mmol) in MeOH (5 mL) was added a solution of sodium methoxide (c=5.4 mol/L in MeOH, 10 mmol) at rt for 48 h. The reaction mixture was poured into a 1N solution of HCl and was extracted with 2 portions of EtOAc, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (heptane/EtOAc, 1:1) to give the title compound (0.28 g, 51%) as a white solid. MS (ISN) 353.1 [(M−H)−], 355.1 [(M+2−H)−].
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)C1CCCCC1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@H](C(=O)N(C)C)C2CCCCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.54 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 256-2 (5.50 mmol, crude form) as starting materials, respectively 0.97 g (Isomer A, colorless powder) and 1.44 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[Br:34]C1C=CC(N)=NC=1>>[Br:34][C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:17][CH:18]=1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Br)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(Br)cn1

Procedure:
The product from Example 11, Part D (150 mg, 0.45 mmol) and 5-bromopyridin-2-ylamine (78 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (151 mg, 69%). 1H NMR (300 MHz, DMSO) δ 8.18 (d, J=2 Hz, 1H), 8.05 (m, 2H), 7.76 (dd, J=9 Hz, 3 Hz, 1H), 7.66 (d, J=7 Hz, 1H), 7.44 (m, 1H), 7.30 (m, 2H), 7.18 (t, J=9, 1H), 7.01 (t, J=7 Hz, 2H), 5.26 (d, J=15 Hz, 1H), 4.69 (m, 1H), 4.23 (d, J=15 Hz, 1H), 2.54 (m, 2H), 1.95 (m, 2H). MS: m/z (MH+) 486 (MH+ 2) 488.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH2:15]Br)[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC(C)=O>[OH:4][C:5]1[CH:14]=[C:13]([CH2:15][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:12]([C:17]([F:18])([F:19])[F:20])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CBr)cc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1O
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(acetyloxy)-4-(bromomethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 47; 309 mg, 0.87 mmol) in acetone (5 ml) was added triethylamine (0.24 ml, 1.74 mmol) and morpholine (0.10 ml, 1.13 mmol) the solution was stirred for 2 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (10 ml), washed with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give the title compound. 300 mg.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O.OC1C2N=NNC=2C=CC=1.[C:29]([O:33][C:34](NC1(C(O)=O)CCCC1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCNCC1>CN(C=O)C>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:4]2([NH:3][C:34](=[O:35])[O:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: CN1CCN(C(=O)C2(N)CCCC2)CC1
Agent: CN1CCNCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)C2(NC(=O)OC(C)(C)C)CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(1-Aminocyclopentyl)(4-methyl-1-piperazinyl)methanone dihydrochloride ##STR204## 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.49 g, 13.0 mmol) was added portionwise to a cooled (4° C.) solution of hydroxybenzotriazole hydrate (1.49 g, 11.0 mmol) and 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (2.29 g, 10.0 mmol) in DMF (15 ml), and the mixture stirred for 30 min. N-Methylpiperazine (1.10 g, 11.0 mmol) was added, the reaction stirred for 30 min. allowed to warm to room temperature and stirring continued for a further 17 h. The reaction mixture was evaporated in vacuo, and the residual yellow oil partitioned between saturated Na2CO3 solution and EtOAc. The layers were separated, the aqueous phase extracted with EtOAc, and the combined organic solutions dried (MgSO4) and concentrated in vacuo. The residual solid was pre-adsorbed onto silica gel and purified by column chromatography upon silica gel using an elution gradient of CH2Cl2 -MeOH-0.880 NH3 (97.5:2.5:0.25 to 90:10:1) and triturated with Et2O to afford tert-butyl 1-[(4-methyl-1-piperazinyl)carbonyl]cyclopentylcarbamate (2.31 g, 7.4 mmol) as a crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:23]=[O:24])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 4′,4-dibromobiphenyl (3.12 g, 10 mmol) in dry THF (50 mL) at −78° C. was added dropwise a solution of n-BuLi (1.6M in hexane, 10 mmol). After addition, the mixture was stirred for 30 minutes at −78° C. Anhydrous DMF (50 mL) was then added and the mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under high vacuum and the residue was taken in water and extracted with dichloromethane (2×50 mL). The combined organic layer were dried (MgSO4) and concentrated. Purification by flash chromatography (ethyl acetate/hexane: 2/8) gave the title compound 152 55% yield. MS (ESI)=261 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[CH2:9][NH:10][C:11](=[O:12])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1]
Reactant: CNCCO
Reactant: O=C=NCc1ccccc1Cl
Solvent: C1CCOC1
Product: CN(CCO)C(=O)NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 2-(methylamino)ethanol (600 mg, 7.99 mmol) in THF (5.0 mL) was added 2-chlorobenzylisocyanate (0.75 mL, 6.66 mmol). The reaction was stirred at rt for 30 min. The mixture was concentrated, re-dissolved in MeOH, filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (950 mg, 49%). LRMS (M+H+) m/z 243.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.[C:14](Cl)(=[O:16])[CH3:15].C(OC(C)C)(C)C.C(O)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COc1cc(NC(C)=O)c2c(c1)OC(C)C2

Procedure:
This compound is prepared according to the procedures of example 10 by reacting 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine with acetyl chloride. M.p. 104° C. (from isopropyl ether/ethyl alcohol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[I-].Cl[CH2:20][CH2:21][S+](C)C.[I-].[Na+].O>C(O)(C)(C)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2([C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:17])[CH2:21][CH2:20]2)[CH:12]=1
Reactant: C[S+](C)CCCl
Reactant: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(c1ccc(Cl)cc1Cl)C1(c2cccnc2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
54 g of 2',4'-dichloro-2-(3-pyridyl)-acetophenone are added portionwise under an inert gas to a suspension of 46.5 g of freshly sublimed potassium tert.butylate in 590 ml of tert.butanol and the reaction mixture is stirred at 45° C. for 2 hours. The mixture is treated at room temperature with 59.5 g of 2-chloroethyl-dimethylsulphonium iodide and a spatula tip of sodium iodide and the mixture is held at 50° C. for 16 hours while stirring vigorously. The mixture is poured into water and extracted three times with 300 ml of diethyl ether each time. The combined organic extracts are washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel with diethyl ether as the eluent and crystallized from diethyl ether/n-hexane. There are obtained 41.7 g of 2,4-dichlorophenyl 1-(3-pyridyl)-cyclopropyl ketone as white crystals, m.p. 83° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>N1C=CC=CC=1>[CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCC1COc1ccc(N)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCN1CCCC1COc1ccc(NS(=O)(=O)CC)cc1

Procedure:
React 4-[(1-butyl-2-pyrrolidinyl)methoxy]benzeneamine with ethanesulfonyl chloride in pyridine in a manner similar to Example 16 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:9]=2)[CH:7]=1.CC(O)=O.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]=O)[CH:43]=1.[BH3-]C#N.[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][N:27]([CH2:48][C:44]3[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=3)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)CNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CN(CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.3 %

Procedure:
To a solution of ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate (420 mg, 0.79 mmol) in EtOH (30 mL) was added AcOH (0.1 mL, 1.75 mmol), pyridine-3-carbaldehyde (126 mg, 1.18 mmol). The mixture was stirred at room temperature for 3 h and NaBH3CN (99 mg, 1.58 mmol) was added. The resulting solution was stirred at 60° C. for 12 h. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3% MeOH in DCM. The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-2): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=24:40 within 12 min; Detector, UV 254 nm. 26 mg product was obtained. This resulted in 25.6 mg (5%) of ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-ethyl)(pyridin-3-ylmethyl)amino]acetate as an off-white solid. LCMS (Method 20) [M+H]+=625.3, RT=1.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.35 (d, 1H, J=6.8 Hz), 8.69-8.68 (m, 2H), 8.39-8.37 (m, 3H), 7.63-7.61 (m, 2H), 7.51 (s, 1H), 7.43 (d, 1H, J=8.8 Hz), 7.31-7.25 (m, 2H), 7.04 (t, 1H, J=73.6 Hz), 4.30-4.27 (m, 2H), 4.07 (q, 2H, J=6.8 Hz), 3.82 (s, 2H), 3.44 (s, 2H), 3.15-3.11 (m, 2H), 1.17 (t, 3H, J=7.2 Hz).