Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C:13]2([C:35]([F:38])([F:37])[F:36])[CH2:17][CH2:16][N:15]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([Cl:33])[CH:19]=3)[C:14]2=[O:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.C(O)C.C(=O)=O>ClCCl.C(OCC)(=O)C>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C:13]2([C:35]([F:36])([F:37])[F:38])[CH2:17][CH2:16][N:15]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([Cl:33])[CH:19]=3)[CH:14]2[OH:34])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2=O)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)cc1Cl
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Tert-butyl (4-{3-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-3-(trifluoro-methyl)-pyrrolidin-1-yl}-2-chloro-benzyl)carbamate (0.36 g) was dissolved in dichloromethane (6 mL). To the resulting solution was slowly added n-hexane solution (1.8 mL) of 1 mol/l diisobutylaluminum hydride while being cooled with ethanol-dry ice under argon atmosphere, and stirring was continued for 30 minutes at the same temperature. Then, n-hexane solution (0.6 mL) of 1 mol/l diisobutylaluminum hydride was further added thereto, and stirring was continued for 30 minutes at the same temperature. Ethyl acetate (1.2 mL) was added, the ethanol-dry ice bath was removed, and stirring was continued for 1 hour. Sodium sulfate decahydrate (3.8 g) was added and stirring was continued for 30 minutes. The precipitates were filtered using Celite and washed with ethyl acetate. The collected filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain tert-butyl (4-{3-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}-2-chlorobenzyl)carbamate (0.30 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8]P(=O)(OC)OC)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:22]1[C:27]2[CH:28]=[C:29]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=3[O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=O)[C:30]([CH3:32])=[CH:31][C:26]=2[O:25][C:24]([CH3:47])([CH3:46])[C:23]1=[O:48])[CH3:21]>C1COCC1.CN1C(=O)N(C)CCC1.C1COCC1>[C:1]([O:5][C:6](=[O:7])[CH:8]=[CH:36][C:35]1[CH:38]=[CH:39][C:40]([O:41][C:42]([F:45])([F:43])[F:44])=[C:33]([C:29]2[C:30]([CH3:32])=[CH:31][C:26]3[O:25][C:24]([CH3:46])([CH3:47])[C:23](=[O:48])[N:22]([CH2:20][CH3:21])[C:27]=3[CH:28]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A flask charged with dimethyl t-butoxycarbonyl-methylphosphonate (0.21 mL, 1.06 mmol) in 2 mL of dry THF/DMPU (10:1) was cooled to −78° C. where 0.52 mL of n-butyl lithium (2.5 M hexane solution, 32 mmol) was added slowly via syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then a solution of Compound 1D (173 mg, 0.43 mmol) in 2 mL of dry THF was added. After warming to room temperature and an additional 20 minutes of stirring, the reaction was quenched with 5 mL of water and passed through a solid phase extraction column (SPE). The column was washed with EtOAc (50 mL) and the collected eluant was evaporated to give crude product which was purified by flash chromatography (EtOAc/Hexanes; gradient 15% to 30%) to give 126 mg (60%) of product as a white solid. MS (electrospray): mass calculated for C27H30F3NO5, 505.21; m/z found 506.2, [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:15]([CH3:21])[CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C([Li])CCC.[C:29](OCC)(=[O:31])[CH3:30]>O1CCCC1>[C:19]([CH:18]([CH2:17][CH2:16][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=2)[CH:10]=1)[CH3:21])[C:29](=[O:31])[CH3:30])#[N:20]
Reactant: CC(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)C(C#N)CCC(C)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 2.5 grams (0.008 mole) of 5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile in 20 mL of tetrahydrofuran was cooled to about -78° C., and 3.2 mL (0.008 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred at -78° C. for 30 minutes, and then 1.1 grams (0.012 mole) of ethyl acetate was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 60 hours. The reaction mixture was partitioned between ethyl acetate and aqueous dilute hydro-chloric acid. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 25% ethyl acetate in hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.9 gram of 3-cyano-2-oxo- 6-[3-(4-trifluoromethylphenyl)phenyl]heptane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:23])[CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCCCC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCC(=O)CC(=O)c1ccc(O)cc1

Procedure:
1-(4-Benzyloxyphenyl)-heptane-1,3-dione (4 g; see step (a) above) was dissolved in toluene (20 ml) and Pd/C (3%; 80 mg) was added. The mixture was stirred at room temperature until hydrogen uptake ceased. After filtration of the catalyst, the solvent was evaporated leaving 2.84 g, 100%, 1-(4-hydroxyphenyl)-heptane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.[O-][CH2:26][CH3:27]>C(O)C1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:21][C:27]2[CH:26]=[CH:4][CH:3]=[CH:2][CH:14]=2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC)c(Cl)c1Cl)C2
Reactant: CC[O-]
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (Example 20, Step C) (5.8 g., 0.016 mole) is dissolved in a mixture of dry benzyl alcohol (50 ml) and methylene chloride (40 ml.) containing amberlite IRA 400 (ethoxide) (5-6 g.). The mixture is stirred magnetically at reflux for four hours and then filtered. The filtrate is concentrated in vacuo to give a yellow solid (5.3 g.) which upon trituration with ethanol and washing with ether yields the product.
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=[O:15])#[CH:2].Cl.Br[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(NCC)C.O.[Cu]I>[CH3:14][O:13][C:12]1[C:3]([C:1]#[C:2][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][N:6]=[CH:5]2
Reactant: Brc1ccncc1
Reactant: C#Cc1c(OC)ccc2c(=O)[nH]ncc12
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: CCNCC
Product: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccncc1
Temperature: 75 °C
Yield: 86 %

Procedure:
A suspension of 5-ethynyl-6-methoxy-2H-phthalazin-1-one (1.9 g, 9.49 mmoles), prepared as described in example 140, 4-bromopyridine hydrochloride (2.214 g, 11.39 mmoles), bis(triphenylphosphine)PdCl2 (133 mg, 0.1998 mmole) and CuI (36 mg, 0.1898 mmole) in diethylamine (40 ml) was heated at 75° C. for 1 hour, cooled, diluted with water (40 ml) and the solid was filtered after 30 minutes under stirring. The solid was suspended in acetone, stirred for 15 minutes, filtered again and dried in oven at 45° C. under vacuum giving 2.263 g of the title compound (yield: 86%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.N1C=CN=C1.[CH:27]1([CH:33]([CH2:48][CH2:49]O)[C:34]([NH:36][CH2:37][C:38]2[C:43]([Cl:44])=[CH:42][C:41]([O:45][CH3:46])=[CH:40][C:39]=2[Cl:47])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[Br:20][CH2:49][CH2:48][CH:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:34]([NH:36][CH2:37][C:38]1[C:43]([Cl:44])=[CH:42][C:41]([O:45][CH3:46])=[CH:40][C:39]=1[Cl:47])=[O:35]
Reactant: COc1cc(Cl)c(CNC(=O)C(CCO)C2CCCCC2)c(Cl)c1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(Cl)c(CNC(=O)C(CCBr)C2CCCCC2)c(Cl)c1

Procedure:
Stir a mixture of triphenylphosphine (3.16 g, 12.06 mmol), bromine (1.91 g, 12.06) and methylene chloride (150 mL) at room temperature for 20 minutes. To the mixture, add a solution of imidazole (0.98 g, 14.48 mmol), 2-Cyclohexyl-N-(2,6-dichloro-4-methoxy-benzyl)-4-hydroxy-butyramide (4.5 g, 12.06 mmol) in methylene chloride (100 mL). Stir the reaction at room temperature for 3.5 hours. Wash the reaction with HCl (1 N), water and brine. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:3 ethyl acetate/hexane to afford 2.5 g. of the title compound. MS (m/z): 436 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[CH3:23][O:24]CCOC>[Pd]>[C:17]1([N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:23](=[O:24])[N:11]3[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOC
Reactant: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1
Agent: [Pd]
Product: O=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-phenyl-1H-1,2,5-triazepine (10.0 g) in 1,2-dimethoxyethane (500 ml) was hydrogenated over 10% palladium on carbon (2 g) at atmospheric pressure and room temperature until theoretical uptake was achieved. The mixture was filtered through Celite and the filter pad was washed with 1,2-dimethoxyethane. The filtrate was evaporated to approximately 100 ml and 1,1'-carbonyl-diimidazole (11 g) was added. The mixture, protected from moisture, was swirled and heated under reflux on a steam bath for 4 hours. The solution was evaporated to dryness. The residue in chloroform was applied to a column (75×5.4 cm) of dry column grade neutral alumina prepacked in chloroform. Elution was with chloroform and monitoring of fractions was by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform-methanol (9:1) as developer. The fractions containing the major component were evaporated to dryness and the residue was crystallized from chloroform-ether; wt. 7.45 g (75%), mp=196°198°. Three crystallizations from the same solvent system gave titled product, mp=198°-199°.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Br[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=1>>[CH3:16][O:15][C:13]1[CH:14]=[C:9]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[OH:7])[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=1
Reactant: C1CCC2OC2C1
Reactant: COc1cc(Br)cc(OC)c1
Product: COc1cc(OC)cc(C2CCCCC2O)c1

Procedure:
Preparation 106 is prepared from cyclohexene oxide and 1-bromo-3,5-dimethoxybenzene in a manner similar to preparation 10. 1H NMR (CDCl3): 6.41 (s, 2H), 6.35(s, 1H), 3.79 (s, 6H), 3.65 (m, 1H), 2.37 (m, 1H), 2.1 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H)1.6-1.2 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:15]([CH3:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N>C1COCC1.CO>[CH3:1][C:2]1[C:15]([CH3:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH:6]=1
Reactant: COCC(=O)Cl
Reactant: Cc1c(Oc2ccnc(N)c2)ccc([N+](=O)[O-])c1C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2C)ccn1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a suspension of 4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-amine (110 mg, 0.424 mmol) in THF (3.0 mL) containing DIPEA (370 μL, 2.12 mmol) at 0° C. was added 2-methoxyacetyl chloride (155 μL, 1.70 mmol) in a single portion. The reaction mixture was warmed to RT for 1 hr and a solution of NH3 in MeOH (7M, 2.0 mL) was added and the resulting mixture maintained at RT for 16 hr and then evaporated in vacuo. The residue was partitioned between DCM (50 mL) and brine (40 mL) and the organic phase was seprated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 20-50% EtOAc in isohexane, gradient elution) to afford N-(4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-yl)-2-methoxyacetamide (94 mg, 67%) as an orange oil; Rt 2.14 min (Method 2); m/z 332 (M+H)+ (ES+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1CNC(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
To 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.97 mmol) and 4-bromo-benzoic acid (996 mg, 4.97 mmol) in DMF (25 mL) was added N-methylmorpholine (655 μl, 5.96 mmol) and HATU (1.89 g, 4.97 mmol). After stirring for 3 hours the reaction was concentrated then diluted with EtOAc and washed with 1N HCl, saturated NaHCO3, and brine. The organic phase was then dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography (20-50% EtOAc-hexanes gradient) to afford 2-[(4-bromo-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.91 g, 4.97 mmol, quantitative yield). LCMS-ESI+: calc'd for C17H24BrN2O3: 383.1 (M+H+). Found: 383.6 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([OH:7])=O.[CH2:16]([NH:18][CH3:19])[CH3:17]>ClCCl.CN(C)C=O>[CH2:16]([N:18]([CH3:19])[C:5](=[O:7])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH3:17]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCNC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(C)C(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
Thionyl chloride (26 mL, 0.36 mol) was added dropwise to a solution of 4-carboxybenzaldehyde (50.0 g, 0.33 mol) in 2000 mL of dichloromethane:N,N-dimethylformamide (4:1 mixture). The mixture was stirred overnight at room temperature. Ethylmethylamine (75.0 g, 1.3 mol) was added dropwise, and stirring was continued at room temperature for 90 minutes. The solvent was removed under vacuum, the residue was dissolved in 500 mL of 0.1M sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum to give 23.8 g (38%) of N-ethyl-4-formyl-N-methylbenzamide as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][NH:4][N:3]=1.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][N:4]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:3]=1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.4 g, 0.0356 mol), 1,1′,1″-(chloromethanetriyl)tribenzene (9.9 g, 0.0356 mol) and triethylamine (7.2 g, 0.0712 mol) were suspended in N,N-dimethylformamide (70.0 mL) and stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of water (30.0 mL) and extracted with ethyl acetate (3×30.0 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (40.0 mL), dried over sodium sulfate and concentrated in vacuo. This crude residue was initially purified via column chromatography eluting with petroleum ether:ethyl acetate (10:1, by volume) and then purified by preparative HPLC to yield title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[H-].[Na+].Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[CH:23][N:24]=2)[N:21]=1.Cl>CN(C=O)C>[CH2:9]([C:3]([CH2:11][CH3:12])([CH2:4][S:5](=[O:6])(=[O:7])[NH2:8])[CH2:2][O:1][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[CH:23][N:24]=2)[N:21]=1)[CH3:10]
Reactant: CCC(CC)(CO)CS(N)(=O)=O
Reactant: Clc1ccc2nccn2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)(COc1ccc2nccn2n1)CS(N)(=O)=O
Temperature: 70 °C
Yield: 62.5 %

Procedure:
To a solution of 3-hydroxy-2,2-diethyl-1-propanesulfonamide (1.0 g) in DMF (70 ml) was added sodium hydride (0.45 g), followed by heating at 70° C. for 30 minutes. The mixture to which 6-chloroimidazo [1,2-b]pyridazine (0.8 g) was added was heated for 5 hours. The reaction mixture was cooled, adjusted to pH 6.0 with 1N-hydrochloric acid and then concentrated. The residue was subjected to a silica gel column chlomatography, eluting with chloroform-methanol (10:1). The corresponding combined fractions were concentrated, thereby affording the above-identified compound (1.0 g).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)C)(C)(C)C.Cl>O1CCCC1.CCOCC>[C:25]1([S:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[CH:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])[CH2:13][CH2:14][CH2:15]3)(=[O:23])=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(CCNC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNCCNC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 96.7 %

Procedure:
[2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester (0.4 g, 0.9 mmol) was dissolved in 20 mL of tetrahydrofuran, and 20 mL of 10% HCl in Et2O was added. The reaction mixture was refluxed for one hour and then cooled. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from EtOH-Et2O to yield 0.3 g (0.87 mmol, 97%) of N-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-N′-methyl-ethane-1,2-diamine as a hydrochloride salt. MS: 345 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH:9]1[C:18]([O:20]CC)=[O:19])(=[O:7])=[O:6].[OH-].[Na+].Cl>O1CCOCC1.CCO>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][CH:9]1[C:18]([OH:20])=[O:19])(=[O:7])=[O:6]
Reactant: CCOC(=O)C1CN(S(C)(=O)=O)CCN1S(=O)(=O)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCN(S(=O)(=O)CCCCl)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A mixture of ethyl (2RS)-1-(3-chloropropylsulfonyl)-4-methanesulfonylpiperazine-2-carboxylate (203 mg) and 1N aqueous sodium hydroxide (0.9 ml) in dioxane (2 ml) and EtOH (1 ml) was stirred for 2 hours at ambient temperature. The mixture was acidified with 1N HCl (0.9 ml) and concentrated in vacuo. The resulting crystals were collected with H2O, and washed with H2O and Et2O to give 165 mg of (2RS)-1-(3-chloropropylsulfonyl)-4-methanesulfonylpiperazine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1B(O)O.Br[C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O.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>[Cl:20][C:17]1[S:16][C:15]([C:3]2[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccc(F)c(B(O)O)c1
Reactant: Clc1ccc(Br)s1
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: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(F)c(-c2ccc(Cl)s2)c1
Yield: 42.1 %

Procedure:
To a solution of 2-fluoro-5-acetylphenylboronic acid (5.00 g, 27.48 mmol) in ACN (80 mL) and H2O (20 mL) were added 2-bromo-5-chlorothiophene (5.43 g, 27.48 mmol), sodium carbonate (2.91 g, 27.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (635 mg, 0.02 mmol). The reaction mixture was refluxed for 3 h. After cooling, ethyl acetate (150 ml) and water (150 ml) were added. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/heptane gave the desired product (2.95 g, 42%).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 37.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.9 mg) was obtained.