Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][C:3]=1[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)c(CN(CCc2ccccc2)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)O)cc1CNCCc1ccccc1
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-amino-3-[[N-(tert-butoxycarbonyl)-N-phenethylamino]methyl]benzoate (2.3 g, 5.4 mmole) in CH2Cl2 (100 mL) at RT was added TFA (25 mL). After 12 hr, the reaction solution was concentrated to an oil and the residue dried under high vacuum overnight. The resulting residue was washed with hexanes and diethyl ether to afford the title compound (2.7 g, 5.4 mmole) as an off-white solid: MS (ES) m/e 271 (M+H-2TFA)+.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:23]=[CH:22][C:12]([CH2:13]P(=O)(OCC)OCC)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[OH:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.CCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12](/[CH:13]=[CH:35]/[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[OH:32])=[CH:22][CH:23]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(C)cc3s2)cc1)OCC
Reactant: O=Cc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccccc4O)cc3)sc2c1
Yield: 58.2 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.30 g, 0.80 mmol) in dry THF (25 ml), potassium t-butoxide (0.19 g, 1.68 mmol) and 2-hydroxybenzaldehyde (0.097 g, 0.80 mmol) in dry THF (10 ml) to give the title compound (0.16 g, 60%) as a yellow solid after work-up and flash chromatography (1:1 Hexane/EtOAc).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([O-])(=O)C.[K+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][CH2:29][C:30]2[NH:39][C:33]3=[N:34][CH:35]=[C:36](I)[CH:37]=[C:32]3[N:31]=2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:36]2[CH:37]=[C:32]3[N:31]=[C:30]([CH2:29][CH2:28][C:24]4[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[CH:26][N:25]=4)[NH:39][C:33]3=[N:34][CH:35]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)NCCO)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 45.2 %

Procedure:
A mixture of 0.42 g of N-(2-hydroxyethyl)-4-bromobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 7 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 15-8:1+1% NH4OH). Concentration of the chromatographically pure fractions and crystallisation from ethanol gives 0.20 g of the title compound as a solid of m.p. 218-220° C. The mass spectrum shows the molecular peak MH+ at 454.1 Da.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[CH3:31]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:31])[CH:24]=2)=[CH:7][C:6]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: COc1ccc(B(O)O)cc1C
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1C

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 3-methyl-4-methoxyphenylboronic acid (Step 2) to give 1,2-difluoro-4-(4-methoxy-3-methylpheny)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 160.5-161.5° C.; NMR (CDCl3) δ 2.11 (S, 3H), 3.04 (S, 3H), 3.79 (S, 3H), 6.63 (d, J=9 Hz, 1H), 6.74 (dd, J=2, 9 Hz, 1H), 6.85 (d, J=2 Hz, 1H), 7.15-7.27 (m, 3H), 7.30 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 2H); MS (FAB) m/z 395 (M+Li)+; HRMS calc'd for M+ 388.0945, found 388.0940. Anal. for C21H18F2O3S: C, 64.94; H, 4.67; F, 9.78. Found: C, 64.59; H, 4.84; F, 9.52.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:23][F:24])[CH:13]([CH3:14])[CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:23][F:24])[CH:13]([CH3:14])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1CN([C@H](C)c2ccccc2)C[C@@]1(CF)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CNC[C@@]1(CF)NC(=O)OC(C)(C)C

Procedure:
To a solution of (3S)-3-(tert-butoxycarbonylamino)-3-fluoromethyl-4-methyl-1-[(1R)-1-phenylethyl]pyrrolidine (200 mg, 0.594 mmol) in ethanol (12 mL) was added 10% palladium-carbon catalyst (containing 52.8% water, 200 mg), and the suspension was stirred in an oil bath at 40° C. for 2 hours in hydrogen gas atmosphere. After removing the catalyst by filtration, the solvent was removed by distillation under reduced pressure to obtain 150 mg (quantitative) of the crude title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[CH2:12]([OH:15])[CH:13]=[CH2:14].C1(N(C)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH2:14][CH2:13][CH:12]=[O:15])=[CH:11][CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: C=CCO
Reactant: Brc1ccc2nccnc2c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: O=CCCc1ccc2nccnc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A mixture of 6-bromoquinoxaline (0.40 g, 1.9 mmol), 2-propen-1-ol (0.260 mL, 3.8 mmol), tris(dibenzylideneacetone)dipalladium (26 mg, 0.029 mmol), tri-tert-butylphosphonium tetrafluoroborate (16 mg, 0.057 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (0.49 mL, 2.3 mmol) in 1,4-dioxane (3.0 mL) was stirred at 40° C. overnight. After cooling to RT, the mixture was filtered, washed with methylene chloride and the filtrate was concentrated. The crude material was purified by chromatography on silica gel with EtOAc in Hexane (0-40%) to afford the desired product (195 mg). LCMS: (M+H)=187.3.
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[C:6]2=[O:14]
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Product: NC(=S)NN=c1c(=O)c2ccc(O)cc2c1=O

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, thiosemicarbazide hydrochloride, reflux for 2 hours.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:19])[CH2:10][S:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16]>C(OCC)C>[O:16]=[C:15]1[CH2:14][CH2:13][CH2:12][S:11][CH:10]1[C:9]([O:8][CH3:7])=[O:19]
Reactant: COC(=O)CCCSCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)C1SCCCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Potassium t-butoxide (1 M in THF) (56.0 mL, 56.0 mmol) was added to an ice cold solution of methyl 4-[(2-methoxy-2-oxoethyl)sulfanyl]butanoate (10.5 g, 50.9 mmol) from (361a), in diethyl ether (200 mL) under nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was partitioned between ethyl ether and water. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to give methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (8.5 g, 82%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1)=[O:6].[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=2)[CH:30]=[CH:31][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:39][C:35]1[N:34]=[C:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:41])([F:25])[F:40])[CH:28]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Br
Reactant: Nc1nccc(-c2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Nc1nccc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-4-methyl-N-(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)benzamide (59 mg, 0.13 mmol) and 4-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (31 mg, 0.13 mmol), KOBut (22 mg, 0.2 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Xantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel was suspended in 1 mL of THF. The reaction mixture was heated in a microwave at 150° C. for 90 min. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder. MS (ESI+) m/z 546.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([N:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(N=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 4-nitrosopiperazine-1-carboxylic acid tert-butyl ester (7.4 mmol) in THF (100 mL) was added LAH (2.5 eq.) portionwise at 0° C. The solution was warmed to rt and stirred overnight, then quenched by the dropwise addition of a saturated solution of potassium sodium tartrate. The aqueous solution was extracted several times with DCM. The organic layer was dried (Na2SO4) and concentrated at 25° C. to afford 4-aminopiperazine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:14][N:15]3[CH:19]=[CH:18][NH:17][C:16]3=[O:20])[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:14][N:15]3[CH:19]=[CH:18][N:17]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:16]3=[O:20])[CH2:12][CH2:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C2(Cn3cc[nH]c3=O)CC2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(Cn3ccn(Cc4ccccc4)c3=O)CC2)cc1OC
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A mixture of 1-[[1-(3,4-dimethoxyphenyl)cyclopropyl]methyl]-1,3-dihydro-2H-imidazol-2-one (1.9 g) in DMF (20 ml) was stirred at RT. Sodium hydride (60%) (0.28 g) was added portionwise over 15 minutes. The mixture was stirred for 30 minutes. A solution of bromomethylbenzene (1.45 g) in DMF (5 ml) was added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether (20 ml). The precipitate was filtered off and dried, yielding 1.3 g (51%) of 1-[[1-(3,4-dimethoxyphenyl)cyclopropyl]methyl]-1,3-dihydro-3-(phenylmethyl)-2H-imidazol-2-one (comp. 21; mp 110.5° C.).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=2[CH3:12].C([Li:17])CCC.CCCCCC>C1COCC1>[CH3:1][C:2]1[CH:10]([Li:17])[C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11]
Reactant: CC1=Cc2c(C)ccc(C)c2C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1C(C)=Cc2c(C)ccc(C)c21

Procedure:
To a solution of 2,4,7-trimethylindene (2.90 g, 18.3 mmol) in 50 ml of THF at 0° C. was added dropwise a 1.6 molar solution of butyllithium in hexane (11.45 ml, 18.3 mmol) in order to produce 2,4,7-trimethylindenyllithium. The solution was stirred for 6 h at room temperature and then added via a cannula to a solution of 1-(9-fluorenyl)-2-bromoethane (5.00 g, 18.3 mmol) in 30 ml THF cooled at -10° C. The mixture was stirred overnight at room temperature and then hydrolyzed with 50 ml of aqueous NH4Cl. The organic phase was separated and the aqueous layer was extracted with ether. The combined organic phases were dried on MgSO4, filtered and the solvent was removed. The residue was crystallized from hot 100% ethanol to give 1.86 g (29%) of 1-(9-fluorenyl)-2-[1-(2,4,7-trimethyl)indenyl]ethane precursor as a white solid; melting point 178-179° C.
Reaction SMILES: CN(C)C=O.[C:6]1([N:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[N:22]=[CH:23][NH:24][C:14]=3[C:13]2=[S:25])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:28]([S:25][C:13]1[N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:14]=1[N:24]=[CH:23][N:22]=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: S=c1c2[nH]cnc2c2cccnc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CSc2c3ncnc-3c3cccnc3n2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
Into 30 ml of dimethylformamide was dissolved 0.79 g (2.5 mmol) of Compound 1 obtained in Example 1. Furthermore, 0.13 g (3.4 mmol) of 60% sodium hydride was added thereto with stirring at room temperature. The mixture was stirred for 1 hour. Then, 0.41 ml (3.4 mmol) of benzyl bromide was added thereto, followed by further stirring for 1 hour. The mixture was cooled with ice and then water was added thereto. The precipitated solid was collected by filtration. The solid was dried, dissolved into chloroform and purified by silica gel column chromatography (eluent: chloroform) to give 0.25 g (24%) of Compound (II) as the first fractions and 0.40 g (38%) of Compound 3 as the second fractions.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[S:36][CH:35]=[N:34][C:33]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:33]3[N:34]=[CH:35][S:36][C:32]=3[CH3:31])=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1scnc1C(=O)NN
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1scnc1-c1nnc2n1CCN(C(=O)c1ccc(Cl)c(F)c1Cl)C2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(250 mg, 0.859 mmol) in dry dichloromethane (DCM) (2147 μl) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (179 mg, 0.945 mmol) was added to the stirred solution and the solution was stirred for 2 hours. 5-methyl-1,3-thiazole-4-carbohydrazide (I123) (162 mg, 1.031 mmol) was then added and the resulting solution was stirred for 65 hours (over the weekend), during which time the solvent evaporated. The residue was redissolved in 1-butanol (2147 p1) and the resulting mixture was heated to 110° C. for 3 hours. The solution was allowed to cool to room temperature before being concentrated under reduced pressure to give a yellow coloured oil. The oil was redissolved in DCM (approx. 30 ml) and the organics were subsequently washed with NaHCO3 (sat. aqueous solution approx. 20 ml) and brine (approx. 20 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil. The oil was chromatographed [SiO2, 0-10% MeOH in DCM] to give a pale yellow coloured oil. The oil was subsequently further purified using MDAP (formic acid method) to give a white coloured solid of desired material in 68 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12]Cl.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(Br)c(CCl)cc1OC
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A solution of 1-bromo-2-chloromethyl-4,5-dimethoxy-benzene (26.01 g, 0.09796 mol) in dry DMF (100 mL) was treated with potassium phthalimide (19.05 g, 0.1029 mol). The resulting slurry was heated to 80° C. while stirring under nitrogen for 4.5 h. The resulting mixture was then cooled to room temperature and allowed to stir 16 h. The resulting mixture solidified, was diluted with water (400 mL) and stirred 1 h. The resulting white precipitate was collected via filtration and washed with water (1 L). The white solid was dissolved in boiling methanol (2 L). The resulting solution was reduced to about 1 L, at which time a precipitate began to form. The resulting slurry was allowed to cool to room temperature then placed on an ice bath. The precipitate was collected via filtration to yield 2-(2-bromo-4,5-dimethoxy-benzyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14]C.F[C:26]1C=C(F)C=CC=1C(O)(CN1C=NC=N1)C(F)(F)SCCO>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:24][CH3:26])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([S:11][CH2:12][CH2:13][OH:14])([F:17])[F:16]
Reactant: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Product: COC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCO

Procedure:
In a similar manner to Example 1 except that 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol was replaced with 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-hydroxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol, the experiment was carried out, whereby 2-{[2-(2,4-difluorophenyl)-1,1-difluoro-2-methoxy-3-(1H-1,2,4-triazol-1-yl)propyl]thio}-1-ethanol was obtained as colorless crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40]([OH:42])=[O:41]>CN(C=O)C>[CH3:44][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:30]([C:24]2([CH3:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])=[CH:43][C:39]=1[C:40]([OH:42])=[O:41]
Reactant: CC1(C(=O)O)CCCCC1
Reactant: Cc1ccc(CN)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)C2(C)CCCCC2)cc1C(=O)O

Procedure:
TBTU (15 mmol; 4.9 g) was added to a mixture of 1-methylcyclohexylcarboxylic acid (15 mmol; 2.2 g), TEA (9.6 mL) and DMF (130 mL) at rt. After 10 min a mixture of 5-aminomethyl-2-methylbenzoic acid (6.3 g crude mixture with NaCl, see step (b) above) was added. After 3 h at rt the reaction mixture was concentrated, water was added and the formed precipitate was washed with water, dried and purified by preparative HPLC. Yield: 3.6 g (83%). MS [M+H]+=290; TLC: Rf=0.49 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I.S([O-])(O)=O.[Na+]>O1CCCC1>[I:36][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: II
Reactant: OC1CCC2(CC1)OCCO2
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: IC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.3 %

Procedure:
To a mixture of 1,4-dioxa-spiro[4.5]decan-8-ol (18.0 g, 114 mmol), imidazole (10.1 g, 148 mmol) and triphenylphosphine (34.3 g, 131 mmol) in tetrahydrofuran (57 ml) was added iodine (33.2 g, 131 mmol) in tetrahydrofuran (57 ml) at 0° C. The mixture was warmed to room temperature, and stirred for 6 hours. The mixture was poured into 10 wt % aqueous sodium hydrogen sulfite, and the organic compound was extracted with hexane (three times). The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved into hexane again, and filtrated to remove triphenylphosphine oxide. The filtrate was concentrated in vacuo to afford 8-iodo-1,4-dioxa-spiro[4.5]decane as a colorless oil (18.1 g, 67.6 mmol, 59%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6](=[O:16])[CH:5]=2)[CH2:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>C(Cl)Cl.[Al]>[Br:17][C:5]1[C:6](=[O:16])[N:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]([CH3:9])[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)cc(=O)n1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: ClCCl
Product: Cn1c(C2CC2)c(Br)c(=O)n1-c1ccccc1
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 5-cyclopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (3.35 g) in methylene chloride (80 mL) was added N-bromosuccinimide (2.78 g). The reaction vessel was wrapped in aluminium foil and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to give a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 4-bromo-5-cyclopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (3.89 g) as a light brown solid. MS (ESI+): 293.1 ([M+H]+).