Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH:15]=[CH:16][C:12]([NH2:11])=[N:13]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: Nc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(N)n2)ccc1Br
Temperature: 95 °C
Yield: 37.3 %

Procedure:
A mixture of 1-bromo-4-iodo-2-methoxybenzene (2.5 g, 7.99 mmol), 3-aminopyrazole (0.797 g, 9.59 mmol), salicylaldoxime (0.219 g, 1.598 mmol), Cu2O (91 mg, 0.479 mmol), and Cs2CO3 (3.9 g, 11.98 mmol) in DMF (8 mL) was degassed with N2 and heated at 95° C. overnight. After cooling to RT, the mixture was filtered through celite and rinsed with EtOAc. The filtrate was washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10%-60% EtOAc in Heptane) to give 1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-amine (800 mg, MS: 270.3 [M+H+]).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:11]=[N:10][CH:9]=[C:8]2[CH3:25])=[O:4].[Li+].[OH-].Cl>C1COCC1.O.O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:13]([F:24])=[C:12]2[C:7]([C:8]([CH3:25])=[CH:9][N:10]=[N:11]2)=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2c(C)cnnc2c(F)c1Nc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnnc2c(F)c(Nc3ccc(Cl)cc3Cl)c(C(=O)O)cc12
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid methyl ester (54 mg, 0.14 mmol) in THF-water (3 mL/l mL) was added 1 N aqueous LiOH (0.30 mL, 0.30 mmol) at room temperature. After 30 minutes, the reaction mixture was adjusted to pH 6-7 with 1 N aqueous HCl, diluted with water, and extracted with EtOAc-THF. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 31 mg (60%) of the crude product (31 mg, 60%), which was used directly without further purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=3[O:24]C)(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.C(Cl)Cl.O>B(Br)(Br)Br>[OH:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)(=[O:14])=[O:13]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(O)c1
Temperature: 25 °C

Procedure:
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-methoxy-4-nitro-benzenesulfonamide (200 mg, 0.55 mmol) was dissolved in 1 M BBr3 in CH2Cl2 (5.0 mL, 5.0 mmol) and the resulting soln was stirred at rt O/N. H2O was the resulting precipitate was isolated by filtration to give the title compound as a white solid: yield; 160 mg (83%). mp 198-199° C.; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.98 (s, 1H), 10.22 (s, 1H), 9.18 (s, 1H), 7.89-7.87 (m, 1H), 7.67-7.63 (m, 2H), 7.48 (s, 1H), 7.23-7.18 (m, 2H), 4.84 (s, 2H); MS (ESI) m/z=349 (M−1, negative); HPLC purity: 95.49% (MaxPlot 200-400 nm), 95.48% (220 nm).
Reaction SMILES: [Na+].[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[CH2:7][C:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)=[C:9]2[C:13]([O-:15])=[O:14])[CH3:4].[C:26]([O:32][CH2:33]I)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(OCC)(=O)C>CN(C)C=O>[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[CH2:7][C:8]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:21]=1)=[C:9]2[C:13]([O:15][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:14])[CH3:4]
Reactant: CNC(=O)c1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt (50 mg) in dry dimethylformamide (1 ml) was cooled with ice, and thereto was added pivaloyloxymethyl iodide (53 mg). The mixture was stirred at the same temperature for 1 hour. To the reaction solution were added ethyl acetate and ice-water, and separated. The organic layer was washed successively with a saturated brine (four times), an aqueous sodium hydrogen carbonate solution, an aqueous sodium thiosulfate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=9/1) to give [(2,2-dimethyl-propanoyl)oxy]methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (27 mg).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)#[N:10].[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[CH2:24][C:22](=[O:23])[O:21]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C>[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[CH:24]([CH2:14][C:13]2[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=2)[C:9]#[N:10])[C:22](=[O:23])[O:21]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: N#Cc1cccc(C=O)c1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2cccc(C#N)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Proline (0.459 g, 3.95 mmol) was added to a mixture of 3-cyanobenzaldehyde (2.59 g, 19.7 mmol) and Meldrum's acid (2.84 g, 19.7 mmol) in ethanol (200 mL). The mixture was stirred at room temperature for 45 minutes and then diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (5 g, 20 mmol) was added. The mixture was stirred for an additional hour at room temperature before being concentrated to dryness. The residue was triturated with isopropanol and filtered to provide the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.446 g, 2.15 mmol) and 6-chloro-3-(piperidin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.593 g, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.330 g (37%) of a colorless foam. FDMS m/e=407 (M+ of free base).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:7][CH:6]=1.[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:9][CH:10]=1)=[O:49]
Reactant: O=C(O)c1cccc(F)c1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)c4cccc(F)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.375 g of benzyl 4-[4-(2-aminoethoxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.094 g of 3-fluorobenzoic acid in 6 ml of dichloromethane and 1.5 ml of N,N-dimethylformamide is admixed with 0.127 g of 3-dimethylaminopropyl ethyl carbodiimide hydrochloride and 0.167 g of 4-dimethylaminopyridine and stirred at room temperature over 18 hours. The reaction mixture is concentrated by evaporation and the residue partitioned between ethyl acetate and water. The organic phase is washed with 1N HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.39 (95:5 dichloromethane-methanol); Rt=5.25.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[O:25]=[C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:32]([C:31]5[C:26](=[O:25])[N:27]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:28]=[CH:29][CH:30]=5)=[O:33])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: O=C(O)c1cccn(-c2ccccc2)c1=O
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)c1cccn(-c2ccccc2)c1=O
Yield: 71 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.460 mmol), N,N-dimethylacetamide (3.0 mL), 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (138 mg, 0.644 mmol), HATU (262 mg, 0.689 mmol) and N,N-diisopropylethylamine (120 μL, 0.689 mmol) and in the same manner as in Example 10, the title compound (171 mg, 71%) was obtained as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[C:11]1([C:17]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:3]=1[N:10]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:9]2
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1c(Br)ccc(Br)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1ccc(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
A solution of 5.3 g (20 mmol) of 3,6-dibromo-1,2-phenylenediamine 1, 4 g (19 mmol) of benzil 2b, 4.2 g of sodium acetate and 150 ml of glacial acetic acid were refluxed for 4 hours. The precipitate was filtered off, washed with 100 ml of water and recrystallized twice from dioxane. Drying under reduced pressure at 50° C. gave the pure product in the form of colorless crystals, which according to HPLC had a purity of about 99.5%. The yield was 6.45 g (73%).
Reaction SMILES: CN.[CH2:3]([N:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[CH3:19])C1=S)C=C>C(O)C.ClCCl>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:19])=[C:12]([NH:8][CH2:9][CH2:10][CH2:11][NH:6][CH3:3])[CH:17]=1
Reactant: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: CNCCCNc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
To an 8.03 M solution of methylamine in ethanol (27 mL) was added the hydrobromide salt of Example 8, Step B (7.5 g). The reaction was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and 1N sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 to 90:10 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.9 g, 84.1%) as a pale orange oil, which was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>N1C=CC=CC=1.[Cu-]=O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([O:34][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#Cc1cccc(O)c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: Cc1ccccc1-c1cc(Oc2cccc(C#N)c2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of 200 mg (0.346 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 84 mg (0.69 mmol) 3-hydroxybenzonitrile in 4 ml pyridine was deoxygenated by three freeze-thaw cycles. After addition of 5 mg (0.04 mmol) copper(I) oxide and 96 mg (0.69 mmol) potassium carbonate under a stream of argon the reaction mixture was heated at reflux for 70 h. Cooling to room temperature was followed by dilution with tert-butyl methyl ether and washing with two portions of 1 M aqueous hydrochloric acid solution. The combined aqueous layers were extracted with tert-butyl methyl ether. The combined organic layers were washed with saturated aqueous sodium carbonate solution and brine, dried with sodium sulfate and concentrated. Column chromatography afforded 174 mg (88%) of the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(C([Cl:16])=O)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5,6-dichloro-nicotinic acid (7.0 g, 0.036 mol, Aldrich), (COCl)2 (50 mL, Aldrich) and DMF (2 drops) was stirred at room temperature for 4 h. The solution was evaporated in vacuo to give the title compound as an orange solid
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][CH:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCC1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-(3-methanesulfonyl-propyl)-piperidine dihydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N4O4S [(M+H)+] 727.2846, observed 727.2848.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([F:13])=[CH:4][N:3]=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:29])[CH:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]3[C:5]([F:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)[CH3:18]
Reactant: COC(=O)C(C)n1ccc2cc(O)ccc21
Reactant: OCCCNc1nc(Cl)ncc1F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)n1ccc2cc(OCCCNc3nc(Cl)ncc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To a solution of 3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-propan-1-ol (Example 80, 0.66 g, 3.20 mmol) and 2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (Example 7, 0.47 g, 2.13 mmol) in dichloromethane (10.80 mL) was added triphenylphosphine (0.85 g, 3.20 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.82 g, 3.20 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h. The desired product (0.54 g, 59%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD3OD) δ 7.85 (d, 1H), 7.27-7.06 (m, 3H), 6.82-6.79 (m, 1H), 6.40 (d, 1H), 5.24 (q, 1H), 4.11-4.07 (m, 2H), 3.70-3.67 (m, 5H), 2.15-2.09 (m, 2H), 1.77 (d, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1>C(#N)C>[Br:1][C:26]1[CH:25]=[C:24]([O:27][CH3:28])[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:22][C:21]=1[CH2:20][N:12]([CH:9]1[CH2:11][CH2:10]1)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c(Br)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 137.2 %

Procedure:
N-Bromosuccinimide (978 mg) was added to a solution of tert-butyl cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]carbamate (6.36 g) in acetonitrile (50 ml) under ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate/=4/1 to 3/1) to give tert-butyl [2-bromo-4-methoxy-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate (3.35 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:19](=O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[NH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]([CH3:24])[C:10]3=[C:13]4[C:18](=[CH:19][C:9]=23)[CH:17]=[CH:16][CH:15]=[CH:14]4)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccc(Cl)cc3)c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1[nH]c(-c2ccc(Cl)cc2)c2cc3ccccc3c1-2
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenyl)indeno[1,2-c]pyrazol-4(1H)-one (0.68 g) was dissolved in N,N-dimethylformamide (30 ml) under nitrogen at 20° C. Sodium hydride (106 mg, of a 60% dispersion in mineral oil) was added and the mixture was stirred for 30 minutes, then iodomethane (0.38 g) was added. The mixture was stirred at 20° C. for 2 hours and then poured into water (50 ml). A yellow solid was collected by filtration and washed with petroleum ether (25 ml). The solid was dissolved in hot ethyl acetate and pre-absorbed onto silica which was applied to the top of the silica column. The mixture was separated by flash column chromatography using dichloromethane/petroleum ether/methanol (50:50:1). Fractions were collected, combined as appropriate, and evaporated to give a solid which was crystallised from ethyl acetate to give 3-(4-chlorophenyl)-1-methylindeno [1,2-c]pyrazol-4(1H-one, m.p. 219-221° C. δH[2H6] DMSO (250 MHz) 4.07 (3H, s, NMe), 7.41 (1H, t, Ar), 7.55 (4H, m, Ar), 7.65 (1H, d, Ar-8-H), 8.13 (2H, d, Ar). The structure was identified by the presence of a Nuclear Overhauser Effect.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[C:21]([CH3:22])=[CH:20][C:10]([CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[O:23][CH3:24].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[OH-].[NH4+]>CN(C=O)C.O>[Si:25]([O:6][C:7]1[C:21]([CH3:22])=[CH:20][C:10]([CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[O:23][CH3:24])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CCOP(=O)(Cc1cc(C)c(O)c(OC)c1)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1cc(C)c(O[Si](C)(C)C(C)(C)C)c(OC)c1)OCC
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Imidazole (7.08 g, 104 mmol) was added portionwise to a well stirred mixture of diethyl (4-hydroxy-3-methoxy-5-methylbenzyl)phosphonate (10 g, 35 mmol) and t-butyldimethylsilyl chloride (7.84 g, 52 mmol) in 25 ml DMF and stirring was continued for 16 h at room temperature. The mixture was poured into water kept at 0° C. to which was added a 25% ammonium hydroxide solution until pH 7 was reached. The aqueous phase was extracted with chloroform, the organic phase was dried over MgSO4. Evaporation of the solvent gave 14 g (100%) of diethyl (4-t-butyldimethylsilyloxy-3-methoxy-5-methylbenzyl)phosphonate as a dark oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34]Br)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CC#N>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:34][CH2:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: CS(=O)(=O)c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCCn2c(C(F)F)cc3c(Cl)c(C#N)ccc32)cc1
Temperature: 100 °C
Yield: 61.6 %

Procedure:
To a solution of 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile (0.019 g, 0.084 mmol) in MeCN (2 mL), under N2, was added Cs2CO3 (0.055 g, 0.17 mmol) and 4-[(2-bromoethyl)oxy]phenyl methyl sulfone (0.047 g, 0.17 mmol). The mixture was heated in a sealed tube at 100° C. for 1 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-70% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.022 g, 61% yield): MS (ES) m/z 425 (M+1).