Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[CH2:31][C:32]([NH:34][C:35]2C=CC(F)=[CH:37][CH:36]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26]O[CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1.Cl.Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1O[C:53]1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=C[N:54]=1.Cl>>[ClH:1].[ClH:1].[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[C:31]2[CH:37]=[CH:36][CH:35]=[N:34][CH:32]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:54]([CH3:53])[CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 36, 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.05 mmol, Compound B of Example 45) was converted the tile compound (10 mg, 32%) as a 3.HCl salt. 1H NMR (CD3OD) δ 9.46 (s, 1H), 9.20 (d, 1H), 9.08 (d, 1H), 8.29 (m, 1H), 7.92 (d, 1H), 7.81 (s, 1H), 7.82 (s, 1H), 7.61 (m, 1H), 7.42 (m, 1H), 4.54 (m, 2H), 3.82-4.05 (m, 10H), 3.05 (s, 3H), 2.51 (s, 3H); MS(ESI+) m/z 506.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[CH3:12][O:11][C:10]1[C:2]([CH:21]=[O:22])=[CH:3][C:4]2[O:8][CH2:7][CH2:6][C:5]=2[CH:9]=1
Reactant: COc1cc2c(cc1Br)OCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1C=O)OCC2
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of 6-bromo-5-methoxy-2,3-dihydrobenzofuran (9.20 g, 40.35 mmol) in THF (50 mL) was dropwise added n-Butyl lithium (24.00 mL, 38.40 mmol) at -78° C. After stirring for 30 min. DMF (5.00 mL, 60.53 mmol) was added and the mixture was allowed to stir at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure. Flash chromatography (1:1 ether/hexane) of the residue afforded 5.42 g (76%) of the title compound as a yellow solid: 1H NMR (250 MHz, CDCl3) d 10.32 (s, 1 H), 6.90 (s, 1 H), 6.82 (s, 1 H), 4.57 (t, 2 H), 3.91 (s, 3 H), 3.25 (t, 2 H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2([C:30](O)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2([C:30]([NH:14][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:16][CH:15]=3)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:22][CH:23]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To a 0° C. suspension of 4-benzyloxyaniline hydrochloride (47.0 g, 200 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (49.1 g, 220 mmol) in CH2Cl2 (400 mL) was added EDCI (38.2 g, 200 mmol). Stirring was continued at rt for 24 h until the reaction was complete. CH2Cl2 was removed under reduced pressure. H2O (300 mL) and MeOH (200 mL) were added, and the resulting mixture was stirred at rt for 30 min. After filtration and wash with H2O, the solid was transferred to another flask containing 300 mL of sat. aqueous NaHCO3 solution. The mixture was stirred for another 30 min. The solid was filtered, washed with water, and dried over night on a lyophilizer, affording cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (75.8 g, 95% yield) as an off-white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16]([CH3:18])=O>>[CH:16]([N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:18])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: CC(C)=O
Product: CC(C)N1CC2CC1CN2C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and using acetone as described in EXAMPLE AAA1, Step A.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][CH:7]2[CH:6]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:5][C:4]1=[O:20].C(N(CC)CC)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].Cl>C(Cl)Cl>[Si:28]([O:1][CH2:2][CH:3]1[CH:8]2[O:9][C:10]([CH3:12])([CH3:13])[O:11][CH:7]2[CH:6]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:5][C:4]1=[O:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(C)OC1CC(=O)C(CO)C2OC(C)(C)OC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)OC1CC(=O)C(CO[Si](C)(C)C(C)(C)C)C2OC(C)(C)OC12
Temperature: 0 °C
Reaction time: 13 h
Yield: 97.4 %

Procedure:
2-Hydroxymethyl-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexanone (765 mg) was dissolved in 7 ml of dry methylene chloride, and 1.2 ml of triethylamine, 55.6 mg of N,N-dimethylaminopyridine and 520 mg of tert-butyldimethylsilyl chloride were added at 0° C., followed by stirring the mixture at 0° C. for 13 hours. The obtained reaction mixture was poured into 1N hydrochloric acid, and extracted with diethyl ether. The extract was washed with a saturated sodium hydrogen carbonate aqueous solution and then with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.04 g of 2-(tert-butyldimethylsilyloxymethyl)-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexanone having the following properties.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:28])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH3:27])[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2S(C)(=O)=O)=[CH:3][CH:2]=1.[CH3:39][O:40][C:41](=[O:50])[C:42]1[CH:47]=[C:46]([OH:48])[CH:45]=[CH:44][C:43]=1[CH3:49].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:39][O:40][C:41](=[O:50])[C:42]1[CH:47]=[C:46]([O:48][C:9]2[N:8]([CH2:7][C:4]3[CH:5]=[CH:6][C:1]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:2][CH:3]=3)[C:12]3[CH:13]=[C:14]([F:28])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH3:27])[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=2)[CH:45]=[CH:44][C:43]=1[CH3:49]
Reactant: Cn1ccc2cc(-c3c(F)cc4c(nc(S(C)(=O)=O)n4Cc4ccc(-c5ccccc5)cc4)c3F)ccc21
Reactant: COC(=O)c1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A solution of 1-biphenyl-4-ylmethyl-4,6-difluoro-2-methanesulfonyl-5-(1-methyl-1H-indol-5-yl)-1H-benzoimidazole (1088 mg, 2.1 mmol), 5-hydroxy-2-methyl-benzoic acid methyl ester (513 mg, 3.1 mmol) and potassium carbonate (580 mg, 4.2 mmol) in DMF (20 mL) was stirred at room temperature under nitrogen. After 18 h, the reaction mixture was transferred to a microwave vial and heated under microwave at 130° C. for 10 min. The cooled reaction mixture was diluted with EtOAc and washed 3 times with saturated ammonium chloride, dried (MgSO4), filtered, and concentrated. Chromatography over silica gel afforded the desired product as a colorless foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]3[C:18](=[O:21])[NH:19][CH2:20][C:16]=3[CH:15]=[C:14]([NH:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][C@@H:24]3[NH:28]C(=O)OC(C)(C)C)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl>CC(O)=O>[NH2:28][C@H:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[NH:22][C:14]1[N:13]=[C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[C:17]2[C:18](=[O:21])[NH:19][CH2:20][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1Nc1cc2c(c(Nc3cccc(S(C)(=O)=O)c3)n1)C(=O)NC2
Agent: Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@@H]3CCC[C@@H]3N)cc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.3 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-(3-(methylsulfonyl)phenylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclopentylcarbamate (16.5 mg, 0.329 mmol) and HCl (1 mL, 32.9 mmol) in HOAc (2 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure and the residue was recrystallized from EtOH—H2O to give the title compound (9.6 mg, 67%). 1H-NMR (DMSO-d6) δ ppm 1.63-1.79 (m, 4H), 20.3-2.06 (m, 1H), 2.19-2.20 (m, 1H), 3.32 (s, 3H), 3.74 (br s, 1H), 4.23-4.28 (m, 2H), 4.45 (br s, 1H), 6.22 (s, 1H), 7.34-7.35 (m, 1H), 7.51-7.58 (m, 3H), 7.73 (br s, 3H), 8.13 (s, 1H), 8.82 (s, 1H), 9.26 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Cl.[F:24][C:25]1([F:29])[CH2:28][NH:27][CH2:26]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:24][C:25]1([F:29])[CH2:28][N:27]([C:16]([C:15]2[CH:19]=[CH:20][C:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:21])[F:22])=[N:4][N:5]=4)[CH:8]=3)=[CH:13][CH:14]=2)=[O:17])[CH2:26]1
Reactant: O=C(O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1)N1CC(F)(F)C1
Reaction time: 24 h
Yield: 57.2 %

Procedure:
4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (52 mg) was dissolved in DMF (2 mL). 3,3-difluoroazetidine hydrochloride (26 mg), diisopropylethylamine (35 μL) and HATU (93 mg) were added sequentially. After 24 h, added additional amounts of Diisopropylethylamine (105 μL) and HATU (279 mg). When the reaction was mostly complete, quenched with ethyl acetate/water, washed with 0.1N HCl, and concentrated NaHCO3. Purified on prep-TLC plate using 5% MeOH/dichloromethane. Isolated 37 mg of (3,3-difluoroazetidin-1-yl)(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)methanone (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@H]1CO

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S)-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[C:11](I)[CH:10]=2)[C:5]([Cl:32])=[CH:4][N:3]=1.[CH:33]([C:35]1[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=1)=[CH2:34]>>[NH2:41][C:37]1[CH:36]=[C:35](/[CH:33]=[CH:34]/[C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:32])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:30]=[CH:29][C:12]=2[O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:40]=[N:39][CH:38]=1
Reactant: C=Cc1cncc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Nc3nc(Cl)ncc3Cl)cc2I)CC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Nc3nc(Cl)ncc3Cl)cc2/C=C/c2cncc(N)c2)CC1
Yield: 99 %

Procedure:
The desired compound was prepared according to the procedure of Example B334, step G, using tert-butyl 4-(2-{4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxy}ethyl)piperidine-1-carboxylate and 5-vinylpyridine-3-amine as the starting materials in 99% yield. LCMS for C29H35Cl2N6O3 (M+H)+: m/z=585.3, 587.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12]Cl)[N:6]=[CH:5]2.[I-].[K+].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: ClCCn1ncc2cc(Br)ccc21
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 70 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromo-1-(2-chloroethyl)-1H-indazole (500 mg, 1.93 mmol), potassium iodide (1.28 mg, 7.71 mmol) and morpholine (1.0 mL, 12 mmol) in NMP (3 mL) in a sealed vial was heated at 70° C. overnight. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, elution gradient of 0 to 60% B over 20 min at 42 mL/min) afforded 4-(2-(5-bromo-1H-indazol-1-yl)ethyl)morpholine (549 mg, 1.77 mmol, 92% yield) as a solid. MS (ESI) m/z 311.98 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.89 (1H, s), 7.81 (1H, s), 7.38-7.42 (1H, m), 7.29 (1H, d, J=8.85 Hz), 4.44 (2H, t, J=6.87 Hz), 3.58-3.63 (4H, m), 2.82 (2H, t, J=6.87 Hz), 2.41-2.48 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:19]=[C:18]([CH3:29])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:29][C:18]1[CH:19]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:21]=[C:16]([CH3:15])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)[CH:31]=1
Reactant: Cc1cc(OCC2(C)COC2)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OCC4(C)COC4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.157 g, 0.816 mmol), (2′,6′-dimethyl-4′-[(3-methyloxetan-3-yl)methoxy]biphenyl-3-yl}methanol (0.231 g, 0.741 mmol) and tributylphosphine (0.298 g, 1.47 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.372 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (0.326 g, yield 82%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd]Cl.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]>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:29])[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:15][CH2:14]1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:29])[CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:17][CH2:18]1
Reactant: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccccc1NC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
4 g (10.12 mmol) of 1-[2-(2-nitrophenyl)amino-2-oxoethyl]-4-(2-oxo-1-benzimidazolinyl)piperidine are dissolved in 40 ml of DMF. After addition of 400 mg of 10% Pd/C (Aldrich), the mixture is hydrogenated at 3 bar until reaction is complete (TLC). The catalyst is filtered off and all solvent is stripped off in a high vacuum. The crude product is coevaporated several times with methanol. The crystals obtained are stirred in methanol, filtered off with suction and dried at 30° C. in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1Cl
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)c(Cl)c2)cc1

Procedure:
The title compound, off-white solid, m.p. 96° C. and MS: m/e=354.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][C:35]=1[CH3:36])=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[O:32][CH:33]=[CH:34][C:35]=2[CH3:36])=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Reactant: Cc1ccoc1C(=O)NNC(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccoc1C(=O)NN(C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F)C(C)C
Yield: 56.9 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (211 mg, 0.64 mmol) and 3-methyl-furan-2-carboxylic acid N′-isopropyl-hydrazide (140 mg, 0.768 mmol) in DMF (3 ml) was treated with diisopropyl amine (0.278 ml, 1.6 mmol) and PyBroP (448 mg, 0.96 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate in hexanes gradient to afford the product as a white solid (180 mg, 57%). MS m/e 495.19 (M+H+)
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].N12CCN(CC1)CC2.O>CN(C)C=O>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:7][CH:6]=1)=[O:14]
Reactant: CC(C)(C)C(=O)Nc1ccc(O)nc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)C(C)(C)C)cn1)c1ccccc1
Yield: 56 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-2,2-dimethyl-propionamide (0.58 g, 3.00 mmol), N -methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 1 hour. Water was added and a thick oil was being formed. The water was decanted and the residue was dissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo yielding the title compound (0.55 g, 56% yield) as a brown oil that solidified upon standing.
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[CH3:20][O:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[CH3:20][O:21][CH2:22][CH2:23][C@@H:24]1[NH:25][CH2:26][CH2:27][N:19]([C:8]2[C:7]3[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:14][C:13]=3[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH2:29]1
Reactant: CC(C)c1cc2c(s1)Nc1ccccc1N=C2N
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: c1ccncc1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)cc32)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 2-isopropyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylamine hydrochloride (0.31 g, 1.04 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (0.30 g, 2.08 mmol) with anhydrous pyridine (4 mL), heat to 110° C. and stir overnight. Cool to ambient temperature to give crude material. Purification by cation exchange chromatography, eluting with solutions of 2M ammonia in methanol, in dichloromethane, (2%, 5%, 10%), and 2M ammonia in methanol, followed by flash chromatography, eluting with a gradient of solutions of 2M ammonia in methanol, in dichloromethane (2-4%), to give the title compound: mass spectrum (APCI, m/e): 385 (M+1); NMR (1H, 300 MHz, DMSO-d6),δ (ppm): 7.60 (s, 1H), 6.86-6.73 (m, 3H), 6.67 (m, 1H), 6.30 (s, 1H), 3.78 (m, 2H), 3.38-3.33 (m, 2H), 3.19 (s, 3H), 3.01-2.60 (m, 6H), 2.39 (m, 1H), 1.51 (m, 2H), 1.17 (d, 6H, J=7.5 Hz).