Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O-:11])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>C1(C)C=CC=CC=1.[Fe+3].O1CCCC1>[O:11]=[C:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCCCCCC(=O)[O-]
Reactant: CCCCCCC[Mg]Br
Agent: [Fe+3]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)CCCCCCCC(=O)OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Under a nitrogen atmosphere, monomethyl azelate (6.70 g, 33.1 mmol), commercially available from Tokyo Chemical Industry Co., Ltd., was dissolved in toluene (60 mL), N,N-dimethylformamide (DMF, 25.6 μL, 0.331 mmol) was added thereto, and the solution was warmed to 60° C. While maintaining the temperature at 60° C., a solution of oxalyl chloride (2.94 mL, 34.8 mmol) in toluene (7.0 mL) was added dropwise over 10 minutes. After completion of the dropwise addition, the mixture was stirred at 60° C. for 2.0 hours. Toluene and oxalyl chloride were distilled off under reduced pressure, and subsequently tetrahydrofuran (THF, 67 mL) was added to distill off the solvent. Under a nitrogen atmosphere, this crude product was dissolved in THF (50 mL), tris(2,4-pentadionato) iron (III) (Fe(acac)3, 0.585 g, 0.166 mmol) was added thereto, and the solution was cooled to −40° C. Subsequently, a dilution of n-heptyl magnesium bromide (1 M solution in THF, 36.4 mL, 36.4 mmol) with THF (30 mL) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was stirred at −40° C. for 1.5 hours. To the reaction solution was added 0.5 M aqueous hydrochloric acid solution (40 mL) to stop the reaction, and the solution was extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layers were combined, washed sequentially with water, a saturated sodium bicarbonate aqueous solution, and a saturated brine and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the resulting residue was purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.2) to obtain methyl 9-oxo-hexadecanoate (No. 4984860; 7.33 g, 78% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[CH3:2].CN(C=O)C.C1C(=O)N([Br:37])C(=O)C1>C(#N)C>[Br:37][C:12]1[C:7]2[NH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[C:8]=2[CH:9]=[N:10][C:11]=1[NH:13][C:14]([NH:16][C@@H:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18])=[O:15]
Reactant: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNc1n[nH]c2c(Br)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-1-(3-(Ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 2; 316 mg, 0.974 mmol) was dissolved in acetonitrile (10 mL) and DMF (2 mL) then NBS (225 mg, 1.266 mmol) was added. The reaction was stirred at room temperature overnight. The solvents were concentrated in vacuo and the residue was purified by flash chromatography (2-10% MeOH/DCM) to give (R)-1-(7-bromo-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C12H19BrN6O [M+1]+ 403. found 403.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:29]=1)(C)C)(C)(C)C>C1COCC1>[CH:35]1([S:34][C:30]2[CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=[CH:32][CH:31]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(SC2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(SC2CCCC2)c1
Reaction time: 18 h
Yield: 92.3 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1M, 6 ml) was added to a solution of tert-butyl{[3-(cyclopentylthio)benzyl]oxy}dimethylsilane (1.09 g) in dry THF (10 ml). The solution was stirred for 18 h under nitrogen and the solvent was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed with water. The organic phase was separated and the solvent evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% dichloromethane-cyclohexane to give the title compound (0.65 g). LCMS RT=3.3 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:28]([O:30]CC)=[O:29])[O:13][CH2:12][C:11]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:28]([OH:30])=[O:29])[O:9][CH2:10][C:11]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH2:12][O:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)OCC(c2ccc(F)cc2)(c2ccc(F)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2ccc(Cl)cc2)OCC(c2ccc(F)cc2)(c2ccc(F)cc2)CO1

Procedure:
2.8 g of ethyl 2-(4-chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylate are refluxed for 7 hours in 60 ml of methanol and 15 ml of water containing 0.7 g of NaOH. After concentrating, the residue is diluted with water and stirred until a solution is obtained. This solution is washed with ether and the aqueous phase is acidified with HCl. The solid formed is filtered off and washed with water and pentane. The product is recrystallized from 100 ml of toluene. (m.p.=228-30° C.; weight obtained 1.9 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[CH2:26]1[CH2:33][O:32][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:29]([CH2:28][CH2:27][CH2:26][CH2:33][OH:32])(=[O:31])=[O:30])[CH2:24][CH2:25]2)[N:3]=1
Reactant: O=S1(=O)CCCCO1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCO)CC2)nc1N
Temperature: 150 °C
Yield: 85.9 %

Procedure:
The mixture of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (100 mg, 0.290 mmol, Example 59), 1,4-butane sultone (81 uL, 0.870 mmol, Aldrich) and triethylamine (41 uL, 0.290 mmol) in tetrahydrofuran (3 mL) was heated at 150° C. for 1 hour using the Smith Creator microwave synthesizer. Upon cooling to room temperature, the reaction mixture was concentrated. Purification of the crude residue by reverse phase HPLC (C18, eluting with water and acetonitrile) gave [4-amino-2-[1-(4-hydroxy-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as white solids (120 mg, 86%). HR-MS (ES, m/z) calculated for C21H29N5O5SF [(M+H)+] 482.Example 221, observed 482.1874.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: C#CCCCO
Product: CS(=O)(=O)c1ccc(C#CCCCO)cc1

Procedure:
Preparation of the title compound with 4-bromophenyl methyl sulphone (5.87 g, 25 mmol) and 4-pentyn-1-ol (2.1 g, 25 mmol) according to the procedure in Example 18 yielded 5.12 g (87%) of yellow oil which was characterized as 5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol: NMR (CDCl3) δ1.88-1.93 (m, 2H), 2.56-2.60 (t, J=6.99, 2H), 3.04 (s, 3H), 3.80-3.84 (t, J=6.15, 2H), 7.56 (d, J=5.1, 2H), 7.85 (d, J=4.8, 2H). MS m/z 239 (M+H cald. for C12H14O3S 238.3).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18](C(OC(C)(C)C)=O)[CH:17]=2)=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]1[C:3]([C:12]([NH:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)n1cc(CNC(=O)c2ncc3cccnc3c2O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1c[nH]c2ccccc12)c1ncc2cccnc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-indole-1-carboxylate from Example 10 (12.0 mg, 0.0029 mmol) in CH2Cl2 (1 ml) was treated with trifluroacetic acid (TFA) (1 ml) and resulting mixture was stirred at room temperature for 1 hr and then the solvent was evaporated in vacuo. The resulting material was dissolved in DMSO (1 ml) and aged for 24 hrs at room temperature. This solution was purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 min/min) to afford the title compound after lyophilization.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:59]([C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OC)(C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([O:25][C:66]([C:65]2[CH:64]=[CH:63][C:62]([N+:59]([O-:61])=[O:60])=[CH:70][CH:69]=2)=[O:67])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (539.00 g, 751.00 mmol) in tetrahydrofuran (6.76 L) is added triphenylphosphine (393.96 g, 1.50 mol) and 4-nitrobenzoic acid (251.02 g, 1.50 mol). The mixture is cooled to 10° C. whereupon diisopropyl azodicarboxylate (40% v/v in toluene, 744.41 mL, 759.30 g, 1.50 mol) is added dropwise over 15 minutes and allowed to warm to 23° C. After 18 hours, the mixture is diluted with methyl tert-butyl ether (2 L), washed sequentially with aq. sat. NaHCO3 (2×2 L) and brine (1 L), and concentrated in vacuo. The residue is slurried in heptane (5 L) at 40° C. for 30 minutes then cooled to 23° C. The resulting solid is filtered and washed sequentially with heptane (2×500 mL), heptane/methyl tert-butyl ether (3×1 L). The combined filtrates are concentrated in vacuo and residue is purified by chromatography (2.5 kg of SiO2; eluent:hexane/ethyl acetate 95:5 to 75:25) followed by recrystallization in heptane (10 L/kg) to yield the title compound as a white solid (273 g, 49% yield).
Reaction SMILES: C([C:4]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH2:5]1)(O)=O.O.C(OC(=O)C)C>CN1CCCC1=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[CH2:5]2)=[CH:19][CH:18]=1
Reactant: O=C1CC(C(=O)O)(c2ccc(F)cc2)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CC(c2ccc(F)cc2)c2ccccc21
Reaction time: 2 h

Procedure:
The following operations are performed under dry nitrogen. A solution of 40.0 gr 3-carboxy-3-(4-fluorophenyl)-indan-1-one in 50 ml N-methylpyrrolidone is heated to 100° C. and stirred for 2 hours at this temperature. The reaction-mixture is cooled and poured into 250 ml water. Subsequent extractive work-up with ethylacetate give the product 3-(4-fluorophenyl)-indan-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16](OCC)=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])[C:8](=[O:15])[C:9]2([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)c(Cl)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)c(Cl)c2C(C)(C)C1=O
Yield: 97.9 %

Procedure:
A solution of ethyl 7,8-dichloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.200 g, 0.456 mmol), glycine tert-butyl ester hydrochloride (0.0993 g, 0.592 mmol), and DIPEA (0.159 mL, 0.911 mmol) in 1,4-dioxane (5 mL) was heated to 120° C. in a 15 mL sealed vessel for 3 hours. The reaction was then diluted with deionized water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with deionized water (50 mL) and then with brine (50 mL). The organic layer was then dried over MgSO4, concentrated, and dried in vacuo to give 0.338 g of the crude product. The crude product was purified by flash column chromatography (silica, 0-50% DCM in hexane) to give the title compound (0.185 g). MS m/e 412 (M−H)−.
Reaction SMILES: Cl[CH2:2][N:3]1[C:15](=[O:16])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:17].[C:18]([O-:21])(=[S:20])[CH3:19].[K+].[I-].[Na+]>CC(C)=O>[C:18]([S:20][CH2:2][N:3]1[C:15](=[O:16])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:17])(=[O:21])[CH3:19]
Reactant: COC(=O)C1C=CCn2c(=O)n(CCl)c(=O)n21
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCn2c(=O)n(CSC(C)=O)c(=O)n21
Yield: 58.5 %

Procedure:
3.24 g (0.0125 mol) of methyl 2-chloromethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate and 2.29 g (0.02 mol) of potassium thioacetate were refluxed together in 400 ml of acetone with a catalytic amount of sodium iodide for 19 hours. The acetone was removed by evaporation and the residue was partitioned between 250 ml of ethyl acetate and 200 ml of saturated sodium chloride solution. The organic layer was separated, dried over magnesium sulphate and evaporated to give a yellow oil. This oil was chromatographed on silica gel using chloroform/ethyl acetate (1:1) for the elution to give 2.19 g (59%) of methyl 2-acetylthiomethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate in the form of a colourless solid of melting point 110°-111° C. (from chloroform/hexane).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[S:14][C:13]([NH:15][C:16](=[O:18])[CH3:17])=[N:12][CH:11]=1.O>CC(C)=O>[Br:9][C:10]1[S:14][C:13]([N:15]([CH3:1])[C:16](=[O:18])[CH3:17])=[N:12][CH:11]=1
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N(C)c1ncc(Br)s1
Yield: 36.8 %

Procedure:
1.9 g (14 mmol) of potassium carbonate and 3.94 ml (63.3 mmol) of methyl iodide are added to a solution of 2.8 g (12.7 mmol) of N-(5-bromothiazol-2-yl)acetamide in 50 ml of acetone. The reaction medium is refluxed for 3 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.1 g (36%) of N-(5-Bromothiazol-2-yl)-N-methylacetamide are obtained.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]([OH:34])=[C:18]([C:20](=[N:28][CH2:29][CH2:30][C:31](O)=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:19]=1.N>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]([OH:34])=[C:18]([C:20](=[N:28][CH2:29][CH2:30][C:31]([NH2:3])=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Cl)cc(C(=NCCC(=O)O)c2ccc(Cl)cc2)c1O
Agent: N
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=NCCC(N)=O)c2ccc(Cl)cc2)c1O

Procedure:
Under a hood, carbonyldiimidazole (5.56 g; 0.0312 mol) is added gradually to a stirred solution of the acid obtained in Example 1 (11 g; 0.0312 mol) in 150 ml of dry tetrahydrofuran. The stirring is continued for 11/2 hours at ambient temperature, and the solution is then poured into 100 ml of liquid NH3 and the whole is stirred until the evaporation of the ammonia has ended (about 3 hours). The residue is evaporated to dryness in vacuo. The residue is dissolved in CH2Cl2 and the methylene chloride solution is washed with water and with a saturated solution of sodium bicarbonate and then dried over MgSO4. Evaporation gives a solid, which is chromatographed on a column (SiO2, AcOEt). The solid obtained is recrystallised from AcOEt (i.e. ethyl acetate) to give a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:33][C@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH:33][C@H:34]5[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]5)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)O)c4)cc3N2)cc1OC
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)N[C@H]5CCCN(C(=O)OC(C)(C)C)C5)c4)cc3N2)cc1OC
Yield: 42.9 %

Procedure:
Example ER-897036 was prepared in two steps from 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinic acid (25 mg, 0.056 mmol) and commercially available (S)-tert-butyl 3-aminopiperidine-1-carboxylate (33 mg, 0.167 mmol) in a manner similar to that of example D-6 to afford intermediate (3S)-tert-butyl 3-(4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinamido)piperidine-1-carboxylate (15 mg, 0.024 mmol, 43% yield). Then, this intermediate (13 mg, 0.021 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-897036 (12 mg, 96% yield.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12](OC)=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 60.7 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (382.94 mg, 60.7% yield) as a white foam. 1H-NMR (CDCl3) δ 7.92 (m, 2H), 7.29 (m, 1H), 6.88 (d, J=8.17 Hz, 1H), 5.83 (m, 1H), 5.42 (m, 1H), 3.90 (m, 1H), 3.72 (s, 3H), 3.25 (m, 2H), 3.00 (t, J=15.0 Hz, 2H), 2.78 (m, 5H), 2.63 (m, 1H), 2.51 (m, 1H), 2.22 (m, 2H), 1.85 (m, 2H), 1.37 (m, 6H). LC/MS=573 (M+H).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[C:15](=[C:23]([OH:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=2)[C:14]1=[O:32])(=[O:12])[CH3:11].C(N(C(C)C)C(C)C)C>ClCCl>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[C:15](=[C:23]([O:31][CH3:6])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=2)[C:14]1=[O:32])(=[O:12])[CH3:11]
Reactant: C[O+](C)C
Reactant: CC(=O)N1C(=O)C(=C(O)c2cccc(I)c2)c2ccc(Cl)cc21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A little at a time, 2.36 g of trimethyloxonium tetrafluoroborate are added to a solution of 3.52 g of 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichloromethane, and the mixture is stirred at room temperature for one hour. Another 1.4 ml of ethyldiisopropylamine and 1.2 g of trimethyloxonium tetrafluoroborate are added, and the mixture is stirred at room temperature for another two hours. The mixture is then extracted with water and the organic phase is dried over magnesium sulphate and evaporated to dryness. The residue is recrystallized from ether and dried at 80° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH:21]=[CH:22]N(C)C)=[CH:16][CH:15]=3.[OH:32][CH2:33][CH2:34][NH:35][NH2:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:35]([CH2:34][CH2:33][OH:32])[N:36]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: NNCCO
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccnn4CCO)ccc3n(C)c21

Procedure:
The process is carried out as in Example 37 above, with the compound from preparation 1.10, 3-(2,4-dichlorophenyl)-6-[3-(dimethylamino)prop-2-enoyl]-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and 2-hydroxyethylhydrazine