Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20].O>CN(C=O)C>[Cl:1][C:2]1[N:12]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:19](=[O:20])[C:18]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:17]=3[Cl:16])=[CH:28][CH:27]=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 16 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with ether to provide the title compound as yellowish brown powder (471 mg, yield 49%).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]1[CH:9]=[C:8]2[CH:10](O)[C:11]3[C:16]([O:17][C:7]2=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.O>C(O)(=O)C>[C:1]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:7]2[C:8]1=[CH:9][CH:4]=[CH:5][CH:6]=2)#[N:2]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
17.5 g (0.268 mol) of potassium cyanide are added in portions to a solution, heated at 50° C., of 24.2g (0.122 mol) of xanthydrol in 420 ml of acetic acid. The reaction mixture is subsequently stirred at 60° C. for 2 hours and then cooled, poured onto 400 ml of water and extracted with ethyl acetate/hexane=1:1. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel using the mobile phase system hexane/ethyl acetate=19:1 and crystallization of the pure fractions from ether/petroleum ether gives 20.2 g (80%) of 9-cyano-xanthene, melting point 101° C. (compound (102), Table 1). The compounds (111), (112), (113), (114), (115), (116) and (117) are prepared analogously to Example 2 from the corresponding substituted xanthydrols and thioxanthydrols, such as, for example, 4-cyclohexyl-xanthydrol, 2-tert-butyl-xanthydrol, 2-nonyl-xanthydrol, 2-(α,α-dimethylbenzyl)-4-methyl-xanthydrol, 2-n-propoxy-xanthydrol, 2,4-diethylthioxanthydrol or 2-dodecyl-thioxanthydrol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=1.CN(C)[CH:20]=[O:21]>>[OH:21][CH2:20][C:17]1[CH:16]=[CH:15][S:14][C:13]=1[C:11]1[S:12][C:8]([CH:7]=[O:6])=[CH:9][CH:10]=1
Reactant: OCc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2sccc2CO)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Phosphorus oxychloride ("POCl3 ") (1 ml) was added into dimethyl formamide (20 ml) slowly under nitrogen gas atmosphere in ice bath and stirred for 1 hour. The dimethyl formamide solution (5 ml) of 5-hydroxymethyl-2,2'-bithiophene (0.5 g) was dropped in slowly. The mixture was stirred for half an hour at room temperature, then the temperature was raised to 50° C. and was further stirred for 3 hours. The reaction solution was poured into potassium carbonate ice water solution. Then the solution was extracted with 100 ml of ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residual solid was purified by column chromatography, eluted with ethyl acetate/n-hexane (3/7). Light yellowish product was recrystallized from ethyl acetate/n-hexane mixture. The melting point of the product was 123°-124° C. The yield was 85%.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)C.[OH-].[Na+]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[C:4]([OH:22])=[O:3])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1

Procedure:
2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid can be prepared by a similar method to that described in the literature (e.g. WO9938845) by reaction of 2-Chloro-5-nitro-benzoic acid ethyl ester [16588-17-3] with 4-Fluoro-phenol [371-35-7] yielding 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester. 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester can then be hydrolysed with sodium hydroxide for example to yield the title compound. MS (m/e): 276.1 (M+H+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)[O:15][CH:10]([C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=32)[CH2:9]1)[C:2]1C=CC=CC=1.C(O)(=[O:27])C>C(O)C.[Pd]>[C:1]([N:8]1[CH2:14][C:13]2([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)[O:15][CH:10]([C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=32)[CH2:9]1)(=[O:27])[CH3:2]
Reactant: CC(=O)O
Reactant: c1ccc(CN2CC3OC(C4OCCO4)(C2)c2ccccc23)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CC2OC(C3OCCO3)(C1)c1ccccc12
Reaction time: 6 h
Yield: 88 %

Procedure:
A suspension of 10% Pd-C (1.42 g) in a solution of the product from Example 29 (9.75 g, 0.0302M) and glacial acetic acid (12 ml) in absolute ethanol (130 ml) was hydrogenated in a Parr apparatus at an initial pressure of 32 psi. After six hours, the catalyst was removed by filtration through Celite and the solvents removed in vacuo. The residue was taken up in CH2Cl2 (50 ml) and treated with acetic anhydride (6.0 ml). After 15 minutes, the mixture was evaporated to dryness and the residue crystallized from Et2O to give the titled compound (7.34 g, 88% yield) as white crystals, mp 122°-123° C. NMR (CDCl3) δ 1.73 ppm (s, 3H, COCH3), 3.0-4.60 (m, 8H, ##STR49## 5.17 (m, 2H, ##STR50## 7.25 (m, 4H, aromatic H). IR (KBr): 1635 cm-1 (C=O). MS: 275 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:10]=3)[NH:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(-c2n[nH]c3ccc(/C=C/c4ccccn4)cc23)cc1
Solvent: CO
Product: Fc1ccc(-c2n[nH]c3ccc(CCc4ccccn4)cc23)cc1
Yield: 47 %

Procedure:
The title compound was prepared as described in Example 141 A, using 5-[(1 E)-2-pyridylvinyl]-3-(4-fluorophenyl)-1H-indazole (0.125 g, 0.4 mmol) in methanol and it was then purified by HPLC (0.060 g, 47% yield): 1H NMR (DMSO-d6) δ 13.14 (br s, 1H), 8.52 (d, 1H), 7.95 (m, 2H), 7.79 (s, 1H), 7.69 (ddd, 1H), 7.42 (dd, 1H), 7.22-7.35 (m, 5H), 3.12 (m, 4H); ES-MS (m/z) 318 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4]C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:2](/[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6](=[O:8])[CH3:7])=[CH:3]\[CH3:4]
Reactant: CC(=O)Nc1ccccc1O
Reactant: CC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C/C=C/Oc1ccccc1NC(C)=O

Procedure:
A heterogenic mixture of commercially available 1-chloro-2-butene (Aldrich, predominantly trans) (453 mg, 0.49 mL, 5.00 mmol), 2-acetamidophenol (756 mg, 5.00 mmol) and potassium carbonate (691 mg, 5.00 mmol) in aceton (10 ml) was heated to reflux over night. After evaporation of the solvent the residue was taken up by ethylacetate and water. Washing of the organic phase with water, 5-proz. sodium hyroxide and brine and evaporation of the solvent afforded the crude which was purified by flash chromatography on silica gel (heptane/EtOAc=3:2). Yield: 732 mg (71%) of a brownish yellow solid. Trans:cis=81:19 (ratio determined by 1H-NMR; 400 MHz, CDCl3):
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)=[CH:32][CH:33]=3)=[N:22][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Reactant: OB(O)c1ccc(OCCn2ccnc2)cc1
Product: Fc1ccc(F)c(CN2CCCNc3ncc(-c4ccc(OCCn5ccnc5)cc4)nc32)c1Cl

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 4-(2-(1H-imidazol-1-yl)ethoxy)phenyl boronic acid as described in example 1 or 30.
Reaction SMILES: Cl.[C:2]([OH:5])(=O)[CH3:3].[CH2:6]([O:13][CH2:14][C@@H:15]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:25][C:19]=2[N:18]=1)[NH2:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][CH2:14][C@H:15]([NH:16][C:2](=[O:5])[CH3:3])[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[CH:25][C:19]=2[N:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)c1nc2cc(Oc3ccc(F)cc3)ccc2[nH]1
Agent: Cl
Product: CC(=O)N[C@@H](COCc1ccccc1)c1nc2cc(Oc3ccc(F)cc3)ccc2[nH]1
Yield: 32 %

Procedure:
Proceeding as in Example 1, but substituting acetic acid hydrochloride and (R)-2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethanamine, gave Compound 60, (R)—N-(2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide (22 mg, 32%). 1H-NMR (400 MHz, CDCl3): σ 7.50 (d, 1H), 7.38-7.30 (m, 5H), 7.13 (br s, 1H), 7.03-6.93 (m, 5H), 6.71 (d, 1H), 5.33 (q, 1H), 4.68-4.58 (m, 2H), 4.19 (dd, 1H), 3.86 (dd, 1H), 2.06 (s, 3H). MS (EI) for C24H22FN3O3. found 420.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.[CH2:30]([N:32](CC)CC)C.CN.O>CN(C)C=O.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH:32][CH3:30])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(=O)(=O)Cl)c3)nc(OC)n2)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonylchloride [0.05 g, Intermediate (10)] and triethylamine (0.064 mL) in dimethylformamide (5 mL) is cooled to 0° C. and the treated with a solution of methylamine in THF (5 mL, 2M). The mixture is allowed to reach room temperature overnight, poured into water (100 mL). This mixture is extracted twice with EtOAc (100 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-N-methyl-benzenesulfonamide [21.5 mg, Example 4(a)]. MS: 429 (M+H), 1H NMR [(CD3)2SO]: δ 8.4 (1H, s); 8.2 (1H, m); 7.85 (1H, d, J=3 Hz); 7.75-7.8 (1H, m); 7.5-7.6 (2H, m); 7.2 (2H, d, J=7 Hz); 6.95 (2H, d, J=7 Hz); 6.6 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 2.8 (2H, t); 2.45 (3H, d, J=2 Hz).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[O:25]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(Oc2ccc(-c3nc4ccccc4o3)cc2)cc1
Yield: 90 %

Procedure:
A mixture of 1.20 g (5 mmoles) of 2-(p-nitrophenyl)benzoxazole, 0.80 g (8.5 mmoles) of phenol, 2 g of potassium carbonate and 15 ml of NMP is stirred and refluxed under nitrogen atmosphere for one hour. The title product is recovered from the resulting solution as described in Example 1. The recovery is 1.15 g (80.4 percent yield). The product has a melting point of 70° C.-71° C. The experiment is repeated using 2-4(p-fluorophenyl)benzoxazole as the reagent and the title product is obtained in 90 percent yield.
Reaction SMILES: I[C:2]1[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]=2[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][CH:27]=1)#[CH:21]>>[C:31]([O:30][C:29]([NH:28][C:24]1[CH:23]=[C:22]([C:20]#[C:21][C:2]2[C:10]3[O:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]=3[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: COC(=O)Cn1c(=O)oc2c(I)cc([N+](=O)[O-])cc21
Product: COC(=O)Cn1c(=O)oc2c(C#Cc3cccc(NC(=O)OC(C)(C)C)c3)cc([N+](=O)[O-])cc21

Procedure:
The desired compound was prepared according to the procedure of Example B5, step C, using methyl (7-iodo-5-nitro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate and tert-butyl (3-ethynylphenyl)carbamate as the starting materials in quantitative yield. LCMS for C23H21N3O8Na (M+Na)+: m/z=490.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:47][C:48]([CH3:50])=[CH2:49]>C1COCC1>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:6]=1)[CH2:49][C:48]([CH3:50])=[CH2:47]
Reactant: C=C(C)CBr
Reactant: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a solution of [2-(3,5-bis-trifluoromethyl-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (150 mg, 0.3 mmol) in THF (5 mL) at −78° C. under argon was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 600 μL, 0.3 mmol). After stirring for 30 minutes, 3-bromo-2-methylpropene (40 mg, 0.3 mmol) was added and stirred for an additional 30 minutes. The reaction mixture was allowed to warm up slowly and stirred for another 30 minutes at 0° C. The mixture was then concentrated and purified by column chromatography on silica gel (20-60% methylene chloride in heptane) to give the product as a white solid (85 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 2H), 8.23 (d, J=8.29 Hz, 2H), 7.96 (s, 1H), 7.69-7.86 (m, 4H), 4.80 (d, J=19.59 Hz, 2H), 4.01 (dd, J=6.78, 9.04 Hz, 1H), 3.74 (s, 3H), 2.97 (dd, J=9.04, 14.69 Hz, 1H), 2.58 (dd, J=6.78, 14.69 Hz, 1H), 1.79 (s, 3H). MS m/e 562.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].C(N(CC)CC)C.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C(Cl)CCl>[Br:18][CH:19]([CH3:23])[C:20]([NH:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:21]
Reactant: CC(Br)C(=O)Br
Reactant: Cc1cccc(Cl)c1CN
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(Cl)c1CNC(=O)C(C)Br
Temperature: -35 °C

Procedure:
A mixture of 35 parts of 2-chloro-6-methylbenzylamine and 30 parts of triethyl amine in 400 parts of ethylene chloride is stirred and cooled to -35°C. While keeping the temperature between -35° and -20° C., there is added dripwise a solution of 50 parts of 2-bromopropionyl bromide in 160 parts of ethylene chloride. Upon completion, the whole is stirred for one hour at room temperature. The reaction mixture is washed with diluted hydrochloric acid and once with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The solid residue is crystallized from a mixture of 400 parts of ethanol and 150 parts of water, yielding 40 parts of N-(2-bromopropionyl)-2-chloro-6-methylbenzylamine; mp. 168° -169° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]([F:12])=[C:10]2[C:6]([C:7]([NH2:21])=[N:8][N:9]2COCC[Si](C)(C)C)=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[F:2][C:3]1[C:11]([F:12])=[C:10]2[C:6]([C:7]([NH2:21])=[N:8][NH:9]2)=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(F)c(F)c21
Agent: Cl
Solvent: CO
Product: Nc1n[nH]c2c(F)c(F)c(-c3ccccc3)cc12
Reaction time: 0.05 h
Yield: 72.7 %

Procedure:
1.1 ml of 2N HCl are added to 661 mg of 6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-amine in 15 ml of methanol. The reaction is subjected to microwaves for 3 minutes at 140° C. After hydrolysis with saturated KH2PO4 solution and extraction with methylene chloride, the solvents are evaporated off and the residue is chromatographed on silica (methylene chloride/ethyl acetate) to give 314 mg of 6,7-difluoro-5-phenyl-1H-indazole-3-amine.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:20]([F:23])([F:22])[F:21])([O:15]CC(O)=O)[C:6]=2[CH:5]=[C:4]([F:24])[CH:3]=1.C(N(C(C)C)C(C)C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>C(O)(C)(C)C.C(O)(=O)C.CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:20]([F:21])([F:22])[F:23])([OH:15])[C:6]=2[CH:5]=[C:4]([F:24])[CH:3]=1
Reactant: O=C(O)COC1(C(F)(F)F)c2ccccc2-c2c(Cl)cc(F)cc21
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: OC1(C(F)(F)F)c2ccccc2-c2c(Cl)cc(F)cc21
Temperature: 0 °C
Yield: 70.4 %

Procedure:
To a mixture of dimethylformamide (184 ml) and an optically active form (36.74 g) of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid was added N-ethyldiisopropylamine (20.9 ml), and the mixture was stirred at 0° C. Thereto, diphenylphosphoryl azide (23.7 ml) was added dropwise over 30 min, and the mixture was further stirred at 0° C. for 2 hr. To the reaction mixture was added acetic acid (2.86 ml) and the mixture was warmed to room temperature. t-Butyl alcohol (96 ml) was added, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (367 ml) was added, placed in a separatory funnel and the mixture was extracted 3 times with toluene (180 ml). The combined organic layer was successively washed with water (180 ml), 1N aqueous sodium hydroxide solution (180 ml), water (180 ml) and saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue, ethanol (37 ml), tetrahydrofuran (37 ml) and 2N aqueous sodium hydroxide solution (37 ml) were mixed, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, water (180 ml) was added, and the mixture was placed in a separatory funnel, and extracted twice with toluene (180 ml). The organic layer was washed twice with water (180 ml) and once with saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2) to give the title compound (21.69 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH2:11]3)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[CH3:23][CH:22]([CH3:24])[CH:17]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:36])[F:37])=[O:35])=[CH:7][CH:6]=3)[CH:9]=2)[CH2:13]1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Product: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4C(F)(F)F)cc3)cc2C1
Yield: 34 %

Procedure:
The compound of example 678 was prepared analogous to the compound of example 7 by reaction of compound of example 673 with 2-trifluoromethyl phenyl isocyanate.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:13]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.O>[CH:21]1([O:20][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:11][C:10]2[O:26][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=3[N:9]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(CC(=O)Nc2c(O)cccc2O)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(Cc2nc3c(O)cccc3o2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of N-(2,6-dihydroxyphenyl)-3-cyclopentyloxy-4-methoxyphenylacetamide (2.10 g) and pyridinium p-toluene-sulphonate (532 mg) in xylene (100 ml) was refluxed, under nitrogen, overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and extracted with dichloromethane (3×75 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml), dried (CaSO4) and evaporated in-vacuo to yield a pale brown solid. The solid was purified by flash chromatography (SiO2 ; dichloromethane;methanol (50:1)) to yield the title compound (1.027 g, 51%) as a white solid (mp 172°-181° C.). δH (250MHz;d6DMSO) 1.53-1.85 (8H,m,4×CH2), 3.70 (3H, s,OMe), 4.18 (2H,s,CH2), 4.72 (1H,m,CH), 6.69 (1H,dd,ArH), 6.82 (1H,dd,ArH), 6.89 (1H,d,ArH), 6.93 (1H,d,ArH), 7.02 (1H,dd,ArH), 7.11 (1H,t,ArH), 10.22 (1H,s,ArOH). m/z 339 (M+), 271 (M--C5H8), 256,242,228,199,149,137,123,94.