Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]12[CH2:22][CH2:21][CH2:20][N:19]1[CH2:18][CH2:17][CH2:16]2>>[N:19]12[CH2:20][CH2:21][CH2:22][C:15]1([CH2:14][CH2:13][N:12]([CH3:11])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18]2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CNCCC12CCCN1CCC2
Product: CN(CCC12CCCN1CCC2)c1ccc([N+](=O)[O-])cc1

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-4-nitrobenzene (1.87 g, 11.9 mmol) and 5-(2-methylaminoethyl)-1-azabicyclo[3.3.0]octane (4.00 g, 23.8 mmol) were employed. In this case, the desired compound was obtained as yellow solids (2.15 g, 62.4%).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([N:25](C(OC(C)(C)C)=O)[S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=3)[CH:16]=[C:11]2[C:10]([C:37]2[C:38]([CH3:51])=[N:39][N:40]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=3)[C:41]=2[CH3:42])=[C:9]1[CH:52]1[CH2:54][CH2:53]1)=O)(C)(C)C.CO.Cl>>[CH:52]1([C:9]2[NH:8][C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=4)[CH:16]=[C:11]3[C:10]=2[C:37]2[C:38]([CH3:51])=[N:39][N:40]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=3)[C:41]=2[CH3:42])[CH2:54][CH2:53]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)c(C2CC2)n3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]c(C4CC4)c(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)cc1NS(C)(=O)=O
Yield: 8.1 %

Procedure:
tert-butyl5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-2-cyclopropyl-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (150 mg) was hydrolyzed with methanol/HCl (5 ml) at 0° C. and purified by prep HPLC to afford 9 mg (8.18% yield) of the pure required product. 1H NMR (CD3OD, 400 MHz): δ 8.32-8.31 (s, 1H), 7.65-7.64 (d, 1H), 7.54-7.7.53 (d, 1H), 7.42-7.37 (q, 1H), 7.06-6.94 (m, 3H), 6.88-6.86 (d, 1H), 5.39 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H), 1.94-1.93 (m, 1H), 1.04-0.90 (m, 4H). MS: m/z=560.0 (M+1), HPLC Purity: 78.69% Method: B.
Reaction SMILES: [OH:1][C:2]1([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[N:20]=3)=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[C:4]([CH3:12])([CH3:11])[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=[N:47]C=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C.O>[OH:1][C:2]1([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[N:20]=3)=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH:5]([C:8]([NH2:47])=[O:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(C3(O)CCC(C(=O)O)C(C)(C)C3)nc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(C3(O)CCC(C(N)=O)C(C)(C)C3)nc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask containing (1S,4S or 1R,4R)-4-hydroxy-2,2-dimethyl-4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)cyclohexanecarboxylic acid (267 mg, 0.366 mmol), EDC (141 mg, 0.733 mmol), HOBt (112 mg, 0.733 mmol) and DIEA (0.320 mL, 1.832 mmol) in DMF (3.66 mL) was added ammonium chloride (59 mg, 1.099 mmol). The solution was stirred at room temperature for 16 hours. Water was added, and the mixture extracted with ethyl acetate (3×). The organic layers were combined, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (6% methanol:dichloromethane) to afford (1S,4S or 1R,4R)-4-hydroxy-2,2-dimethyl-4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)cyclohexanecarboxamide as a white solid. MS ESI calcd. for C26H29F3N5O2 [M+H]+ 500. found 500. 1H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.10 (d, J=1.7 Hz, 1H), 8.54 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.33 (dd, J=8.4, 2.3 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.17 (d, J=5.2 Hz, 1H), 7.16 (s, 1H), 6.54 (s, 1H), 4.99 (s, 1H), 2.63-2.57 (m, 1H), 2.36 (d, J=13.6 Hz, 1H), 2.34 (s, 3H), 2.10 (t, J=5.1 Hz, 1H), 1.96-1.90 (m; 1H), 1.75-1.65 (m, 1H), 1.41-1.35 (m, 1H), 1.32 (d, J=13.4 Hz, 1H), 1.09 (s, 3H), 0.61 (s, 3H). rhSyk IC50=23 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH:11]=[N:10][CH:9]=[CH:8][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.COC1C=CC([N+]([O-])=O)=C2C=1C=NC=C2.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:40]=[CH:39][C:34]([CH2:35][N:36]=[C:37]=[O:38])=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:37]([NH:36][CH2:35][C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:42])[F:41])=[CH:40][CH:39]=2)=[O:38])=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2
Reactant: COc1ccc(N)c2ccncc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Agent: COc1ccc([N+](=O)[O-])c2ccncc12
Product: COc1ccc(NC(=O)NCc2ccc(C(F)(F)F)cc2)c2ccncc12

Procedure:
Prepared from 8-methoxyisoquinolin-5-amine which was prepared from 8-methoxy-5-nitroisoquinoline (J. Het. Chem. 37(5), 1293) according to Description 43 and immediately used in reaction with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]2=[O:19].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH:39]=[CH2:40].N(C)(C1CCCCC1)C1CCCCC1>CN(C=O)C.C(OCC)(=O)C.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd]>[CH3:12][C:7]1[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2](/[CH:40]=[CH:39]/[C:38]([O:42][CH2:43][CH3:44])=[O:41])[CH:3]=2)[N:8]=1
Reactant: Cc1nc2ccc(Cl)cc2c(=O)n1-c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc2nc(C)n(-c3ccccc3)c(=O)c2c1

Procedure:
The target solid of step 1 (4 g, 14.78 mmol), Herrmann's palladacycle (0.277 g, 0.30 mmol), and [(t-Bu)3Ph]BF4 (0.171 g, 0.60 mmol) mixed in DMF (40 mL) was added with ethyl acrylate (1.58 mL, 14.76 mmol) and Cy2NMe (3.27 mL, 14.78 mmol) and irradiated with microwave at 150° C. for 30 min (two times). The resulting mixture was evaporated to get dark green residue. The residue was suspended in ethyl acetate (50 mL) and washed with water (3×50 mL). The organic layer dried over MgSO4 was evaporated to get crude yellow solid of target compound of step 2. The yellow solid was put to step 3 without further purification.
Reaction SMILES: [N+:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8])#[C-:2].[C:15]([CH2:17][C:18]([OH:20])=O)#[N:16].CN(C)C=O.CS(Cl)(=O)=O>O.C(O)(C)C.O>[C:15]([CH2:17][C:18]([N:9]([CH3:10])[C:7](=[O:8])[NH:6][CH2:5][C:4]1[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=1[N+:1]#[C-:2])=[O:20])#[N:16]
Reactant: [C-]#[N+]c1ccccc1CNC(=O)NC
Reactant: N#CCC(=O)O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: [C-]#[N+]c1ccccc1CNC(=O)N(C)C(=O)CC#N
Temperature: 25 °C
Yield: 68 %

Procedure:
Under nitrogen atmosphere, 1-(2-isocyanobenzyl)-3-methylurea (98.4 g) and cyanoacetic acid (80.0 g) was added to N,N-dimethylformamide (836 ml). The mixture was stirred at room temperature and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at this temperature. The mixture was stirred at room temperature for 4 hrs, cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added drop wise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 3-(2-cyano-acetyl)-3-methyl-1-(2-isocyanobenzyl)-urea with 68% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[CH2:23]([NH:30][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][O:4][C:3]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=2[Cl:1])[CH:10]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (68 mg, 0.2 mmol), benzylamine (0.032 ml, 0.3 mmol) in DMF 3.0 mL was added EDC (57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtoAC:MeOH=15:3:1) to give N-benzyl-3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzamide as a white solid (12 mg, 14% yield).
Reaction SMILES: [BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[C:34](=[O:36])[CH3:35])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][C:26]=2[CH:34]([OH:36])[CH3:35])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1oc2ccccc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(O)c1oc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Tetrabutylammonium borohydride (750 mg, 2.91 mmol) was added to a solution of 1-(3-phenylbenzofuran-2-yl)ethanone (459 mg, 1.94 mmol) in THF (9 mL) and IMS (1 mL) and the mixture stirred at RT for 1 h. The reaction mixture was quenched by addition of MeOH and volatiles were removed in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording the title compound as an oil (452 mg, 98%). LCMS (Method C): RT 3.57 min [M-OH]+ 221.1
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[C@@H:20]([CH:23]([CH3:24])[CH3:25])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:26][CH:27]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OCc2ccccc2)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)- N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (11.3 mg, 29.2 μmol) in CH2Cl2 (1 mL) was added benzyl chloroformate (11.7 μL, 3.0 M in toluene), triethylamine (6.1 μL, 43.8 μmol) and 4-dimethylaminopyridine (50 μg, 4.09 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 30% EtOAc in hexanes, gradient to 100%), then further purified by reverse-phase HPLC to yield 14.9 mg of benzyl (S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as an HCl salt (16, 91%). LC-MS tR=0.91 min in 1 min chromatography, MS (ESI) m/z 522.5 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.00 (s, 1H), 8.34 (s, 1H), 7.87 (dd, J=1.6 Hz, 6.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.42 (dd, J=1.6 Hz, 8.4 Hz, 2H), 7.33 (m, 3H), 5.20 (m, 3H), 4.96 (m, 1H), 4.71 (m, 3H), 3.20 (q, J=7.6 Hz, 2H), 2.57-2.36 (m, 1H), 1.19 (t, J=7.6 Hz, 3H), 1.00 (dd, J=6.8 Hz, 16.0 Hz, 3H), 0.78 (dd, J=6.8 Hz, 25.6 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1>[C:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NCCc2ccccc2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)NCCc2ccccc2)cc1
Yield: 91.5 %

Procedure:
To a solution of 23 (0.6 g, 1.7 mmol) in dioxane (8 ml) 20% NaOH is added (13 ml) and the mixture is refluxed for 1.5 hours. The solvent is concentrated under reduced pressure and the aqueous phase is added with 20% NaOH to pH=7. The resulting solid is filtered under reduced pressure, washed with water and dried to give compound 24 as white solid (0.43 g, 83% yield).
Reaction SMILES: C[O-].[Na+].[C:4]1([NH:10][C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH3:16][C:15]1[N:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:11](=[O:12])[NH:13][CH:14]=1
Reactant: C#CCNC(=O)Nc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c[nH]c(=O)n1-c1ccccc1
Yield: 55.6 %

Procedure:
0.8 ml of 5.35 N sodium methoxide is added to a suspension of 10 g (0.062 mol) of N-phenyl-N′-propargylurea in 140 ml of toluene. The mixture is heated at the reflux temperature for 4 hours. The solvent is evaporated and then the solid residue is taken up in acetone. The product precipitates, it is filtered, washed with a small amount of acetone and dried under vacuum at 50° C. 6 g of product are obtained. (m.p.=207° C.).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][CH3:56]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:52]([CH2:53][CH2:54][O:55][CH3:56])[CH2:51][CH2:50][O:49][CH3:48])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: COCCNCCOC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(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]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with bis-(2-methoxy-ethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H55Cl2N6O5 [(M+H)+] 781.3606, observed 781.3603.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].Cl[C:26]1[N:30]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[C:29]2[CH:37]=[CH:38][CH:39]=[CH:40][C:28]=2[N:27]=1>C(Cl)Cl.[Cu]>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:26]2[N:30]([CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:29]3[CH:37]=[CH:38][CH:39]=[CH:40][C:28]=3[N:27]=2)[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@H](N)C[C@@H]2Cc2ccccc2)c1
Reactant: Clc1nc2ccccc2n1Cc1cccs1
Agent: [Cu]
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](Nc3nc4ccccc4n3Cc3cccs3)C[C@@H]2Cc2ccccc2)c1
Yield: 94 %

Procedure:
(±)-cis-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinamine (1.2 g), 2-chloro-1-(2-thienylmethyl)-1H-benzimidazole (2.24 g) and copper (0.6 g) were stirred at 150° C. for 5 hours. The mixture was taken up in CH2Cl2 and filtered. The filtrate was washed with diluted NH4OH and stirred. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN, yielding 1.87 g (35%) of (±)-cis-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-N-[1-(2-thienylmethyl)-1H-benzimidazol-2-yl]-4-piperidinamine (comp. 76; mp. 201.4° C.).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1Cl

Procedure:
Using 2,3-dichloro-4-fluorobenzonitrile (334 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (397.3 mg) and lithium carbonate (312 mg), the title compound was obtained as white crystals (yield: 427 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20]O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]1(=[O:69])[NH:63][C:62](=[O:64])[C:61]2=[CH:65][CH:66]=[CH:67][CH:68]=[C:60]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][N:63]3[C:59](=[O:69])[C:60]4[C:61](=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:62]3=[O:64])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29]5[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=5)=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 326.4 %

Procedure:
To a solution of compound (ii) (5 mg, 0.009 mmol), triphenylphosphine (3.6 mg, 0.014 mmol) and phthalimide (2.0 mg, 0.014 mmol) in THF (0.5 mL) was added diisopropyl azodicarboxylate (2.7 μL, 0.014 mmol) at 0° C. After the mixture had been stirred at RT for 3.5 h, more triphenylphosphine (3.6 mg, 0.014 mmol), phthalimide (2.0 mg, 0.014 mmol) and DIAD (2.7 μL, 0.014 mmol) were added and stirring was continued at RT for a further 40 min. The solvent was removed in vacuo and the residue was purified by preparative LCMS (5-50-100% ACN in 0.1% aqueous formic acid) to afford 5-cyclopropyl-6-[3-(1,3-dioxoisoindolin-2-yl)propyl-methylsulfonyl-amino]-2-[4-(4-fluoroanilino)phenyl]-N-methyl-indazole-3-carboxamide (iii) as a white solid (20 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.[N+:31]([C:34]([CH3:36])=[CH2:35])([O-:33])=[O:32]>C(#N)C.O1CCCC1>[N+:31]([CH:34]([CH3:36])[CH2:35][O:9][CH:3]1[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]1([CH3:10])[CH3:1])([O-:33])=[O:32]
Reactant: C=C(C)[N+](=O)[O-]
Reactant: CC1(C)CCC(C)(C)C1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(COC1C(C)(C)CCC1(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2,5,5-Tetramethyl-1-cyclopentanol is added to a dry flask under argon at 0° C. Dry tetrahydrofuran is added with a syringe. Sodium hydride (60% dispersion in oil) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is added with vigorous stirring over a 10 minute period. After completion of the reaction as judged by thin layer chromatography, it is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield 1-(2-nitropropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([O:19][CH2:20][CH3:21])=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.Cl>[OH-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([O:19][CH2:20][CH3:21])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)oc1OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOc1oc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 100 °C
Yield: 67.6 %

Procedure:
A suspension of ethyl 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylate (2.10 g, 7.1 mmol) in 1M aqueous potassium hydroxide and heated to 100° C. for 6 hours. The mixture was then cooled to 0° C. and acidified to pH 3 by 2M aqueous HCl. The resulting white solid was filtered, washed with water and dried in a vacuum oven to afford 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylic acid (1.28 g, 4.8 mmol, 67%). 1H NMR (CD3OD) δ 1.52 (3H, t), 4.61 (2H, q), 7.19 (2H, t), 7.61 (1H, m). LCMS (1) Rt: 1.09 min; m/z (ES+) 270.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([O:26][CH2:27][CH2:28][O:29][C:37](=[O:38])[C:36]4[CH:35]=[C:34]([O:33][CH3:32])[C:42]([O:43][CH3:44])=[C:41]([O:45][CH3:46])[CH:40]=4)[CH2:24][CH2:25]3)[C:5]=2[CH:4]=1
Reactant: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)OCCOC2CCN(CCCN3c4ccccc4Sc4ccc(C(F)(F)F)cc43)CC2)cc(OC)c1OC
Yield: 32.9 %

Procedure:
Using the procedure of Example XXXV, 18.7 g (0.04 mole) of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-piperidino)-propyl]-phenothiazine (prepared in Example XXIII) and 9.2 g (0.04 mole) of 3,4,5-trimethoxy-benzoyl chloride were reacted to obtain 8.5 g (33% yield) of 2-trifluoromethyl-10-[ 3{ 4-[2-(3,4,5-trimethoxy-benzoyloxy)-ethoxy]-piperidino}-propyl]-phenothiazine as a clear amber oil