Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]3[NH:12][C:13](=[O:22])[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:26][C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1>CN(C=O)C>[CH3:32][N:30]1[N:29]=[N:28][C:27]([CH2:26][O:22][C:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:10]3[N:11]([C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][N:9]=3)[N:12]=2)=[N:31]1
Reactant: Cn1nnc(CCl)n1
Reactant: O=c1[nH]n2c(-c3ccccc3)nnc2cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(COc2nn3c(-c4ccccc4)nnc3cc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To the product from Example 73, Step a (0.15 g, 0.52 mmol) in anhydrous DMF (5 ml) was added sodium hydride (60% dispersion in oil, 31.2 mg, 0.780 mmol) and the mixture was stirred under nitrogen at room temperature for 45 min then at 80° C. for another 20 min. After allowing to cool, a solution of 5-chloromethyl-2-methyl-2H-tetrazole (Moderhack, D., Chem. Ber., 1975, 108, 887-896) (0.103 g, 0.780 mmol) in anhydrous DMF (4 ml) was added and the mixture was stirred at room temperature under nitrogen for 1.5 h, then at 80° C. for 17 h. The mixture was then partitioned between water (30 ml) and ethyl acetate (40 ml). The aqueous layer was further extracted with ethyl acetate (9×40 ml) and the combined organic extracts were dried (MgSO4), and evaporated in vacuo. The residue was recrystallised from EtOAc—CH2Cl2—MeOH to afford 0.1002 g (50%) of the title compound as a white solid: mp 228-233° C.; 1H NMR (360 MHz, CDCl3) δ 4.36 (3H, s), 5.79 (2H, s), 7.47-7.60 (8H, m), 8.07 (1H, s), 8.48 (2H, m); MS (ES+) m/e 385 [MH]+. Anal. Found C, 62.01; H, 4.13; N, 28.92. C20H16N8O. 0.17H2O requires C, 62.00; H, 4.25; N, 28.92%.
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:32])[C:10]2[O:16][C:15]3[C:17]([Cl:28])=[CH:18][C:19]([N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl)=[CH:20][C:14]=3[CH2:13][S:12](=[O:30])(=[O:29])[C:11]=2[CH:31]=1)=[O:6]>CO>[Cl:28][C:17]1[C:15]2[O:16][C:10]3[C:9]([CH3:32])=[CH:8][C:7]([C:5]([OH:4])=[O:6])=[CH:31][C:11]=3[S:12](=[O:29])(=[O:30])[CH2:13][C:14]=2[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:2]([CH3:1])[CH2:26][CH2:25]2)[CH:18]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCl)cc(Cl)c1O2
Reactant: CN
Solvent: CO
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCN(C)CC3)cc1CS2(=O)=O

Procedure:
Methanolic methylamine solution (20% v/v, 6 mL) was added to a solution of Example 102 (0.330 g, 0.69 mmol) in methanol (2 mL) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 100° C. for 6 h. It was brought to room temperature, flushed with N2 gas, treated with chilled water and dilute HCl to neutral pH. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, MeOH/CHCl3) to obtain the title compound as an off white solid. Yield: 0.260 g (86.37%). 1H NMR (DMSO-d6): δ 2.40 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.72-2.75 (m, 4H, 2CH2), 3.30-3.35 (m, 4H, 2CH2), 5.10 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.10 (s, 1H, Ar) and 8.25 (s, 1H, Ar); MS: m/e (ES+) 436 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:29][C:26]2[CH:25]=[CH:24][C:23]([C@H:22]3[C:15]4=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]4[CH2:19][CH2:20][CH2:21]3)=[CH:28][CH:27]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1ccc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of (4-ethylphenyl)boronic acid (802 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg), and powdered 4A MS (5.00 g) in MeCN (18 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (132 mg) as a white solid.
Reaction SMILES: [NH:1]([C:8](=[O:24])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[NH2:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:24])[CH2:11][CH2:12]1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CC(=O)Nc2ccccc2)CC1

Procedure:
The product of stage 1 (0.28 g; 0.84 mmol) is stirred over night at r.t. with 10 mL 10% TFA in DCM. The solvent is removed to give 2-(4-amino-1-piperidyl)-N-phenyl-acetamide as a TFA salt (I.1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].C1COCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[CH2:31]([N:33]([CH2:34][CH3:35])[C:17]([C:14]1([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4]2)[CH2:12][CH2:13]1)=[O:18])[CH3:32]
Reactant: CCNCC
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 65 μL of 2.0 M diethylamine/THF (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL of NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield the desired 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid diethylamide:.MS (ES) M+H expected=477.3, found=477.4.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]([CH3:88])[CH2:59][CH2:60][C@@H:61]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([S:77]([NH2:80])(=[O:79])=[O:78])=[CH:73][C:72]=1[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:80][S:77]([C:74]3[CH:75]=[CH:76][C:71]([NH:70][C@H:61]([CH2:60][CH2:59][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:54])[CH3:53])([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH3:88])[CH2:62][S:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[C:72]([S:81]([C:84]([F:86])([F:87])[F:85])(=[O:82])=[O:83])[CH:73]=3)(=[O:78])=[O:79])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 84.7 %

Procedure:
The title product (110 mg, yield: 88%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 32 utilizing 4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 56.7 mg, 0.11 mmol) and (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 28, 75 mg, 0.10 mmol) as starting materials. The title product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→30% EtOAc/hexanes).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1.[C:36](#[N:38])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:36]([C@@H:10]1[CH2:11][CH2:12][N:8]([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9]1)#[N:38]
Reactant: CS(=O)(=O)O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: N#C[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 65 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
(3S)-1-Diphenylmethyl-3-mesyloxypyrrolidine (1.25 g) was dissolved in acetonitrile (1.75 mL). Tetrabutylammonium cyanide (1.87 g) was added to the solution, and the mixture was stirred at 65° C. for 12 hours. Saturated sodium hydrogencarbonate (7 mL) and toluene were added dropwise to the reaction mixture, whereby the organic layer was extracted. The organic layer was washed with water and then dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystals. The residue was subjected to silica gel chromatography, to thereby give the target compound (0.766 g, yield 77.4%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.BrC1C=CC(S(O[CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)(=O)=O)=CC=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)[CH2:13][CH2:14]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2cccc(C)c2C)CC1)O3
Temperature: 70 °C
Yield: 89.9 %

Procedure:
A mixture of 1-(2,3-dimethylphenyl)-piperazine (1.13 g, 5.94 mmol) and [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzene-sulfonate (871 mg, 1.93 mmol) in anhydrous DMSO (10 mL) was heated overnight at 70° C. The reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (50% EtOAc/hexanes) afforded 700 mg (90%) of the title compound as a white solid: mp 112–113° C.; MS (ESI) m/z 404 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([OH:11])=O)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[CH3:24].N1C=CC=CC=1>ClCCl.CO>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Br:16])=[C:18]([CH3:24])[CH:19]=2)=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnoc1C1CC1
Reactant: Cc1cc(N)ccc1Br
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)c2cnoc2C2CC2)ccc1Br
Temperature: 0 °C

Procedure:
3.33 g (21.7 mmol) of 5-cyclopropylisoxazole-4-carboxylic acid and 25 ml of thionyl chloride were refluxed for 90 minutes and after the thionyl chloride was evaporated in vacuo, the residue was azeotroped twice with toluene. 4.0 g (21.7 mmol) of 4- bromo-3-methyl-aniline were dissolved in 125 ml of dry dichloromethane, cooled to 0° C. and the acid chloride and 2.4 g (30 mmol) of pyridine each dissolved in 10 ml of dichloromethane, were added dropwise simultaneously. After stirring for thirty minutes at 0° C., the reaction mixture was washed 3 times with 75 ml of brine, dried over MgSO4 and the dichloromethane was removed in vacuo to yield a brown oil. Flash column chromatography (2% MeOH, 98% CH2Cl2) yielded a pale brown oil which crystallized upon standing. Crystallization from ethanol/water yielded the desired product as cream needles melting at 133°-135° C.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[O:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:18]=[C:17]4[C:33]3[N:38]=[C:37]([N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]4[CH3:45])[CH:36]=[CH:35][N:34]=3)=[N:12][N:13]=2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:45][CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][N:39]1[C:37]1[CH:36]=[CH:35][N:34]=[C:33]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([C:11]4[O:10][C:9]([NH2:8])=[N:13][N:12]=4)[CH:15]=3)[N:19]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=3)(=[O:25])=[O:24])[CH:18]=2)[N:38]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(N5CCCCC5C)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N4CCCCC4C)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Temperature: 120 °C

Procedure:
N-(4-Methoxybenzyl)-5-(3-(4-(2-methylpiperidin-1-yl)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (313 mg, 0.482 mmol) in a 20 mL glass microwave tube was dissolved in TFA (3.00 mL). The tube was sealed, and the solution was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 20 min. The excess TFA was removed, the crude residue treated with 1N NaOH and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give the crude material: MS (ESI, pos ion) m/z 530.2 (M+1).
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[NH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:1]1[CH:5]=[C:4]([CH2:6][O:7][N:34]2[C:38](=[O:39])[C:37]3[C:36](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:35]2=[O:44])[NH:3][CH:2]=1
Reactant: O=Cc1cnc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cnc[nH]1
Reaction time: 4 h

Procedure:
(3H-Imidazol-4-yl)-methanol (90 mg, 0.92 mmol) obtained by reducing 3H-imidazole-4-carboaldehyde (commercial product) with lithium aluminum hydride in THF was mixed with PPh3 (245 mg, 0.94 mmol), N-hydroxy-phthalimide (153 mg, 0.94 mmol), and diisopropyl azodicarboxylate (189 mg, 0.94 mmol) in anhydrous THF at 0° C. under a nitrogen atmosphere, and the mixture was stirred. After 4 hours, the reaction mixture was purified by silica gel chromatography to give 2-(3H-imidazol-4-ylmethoxy)-isoindol-1,3-dione (30 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([NH:16][C:17]3[C:26]4[CH2:25][C:24]([O:27]CC)=[CH:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:26]=3[CH2:25][C:24](=[O:27])[CH2:23][CH2:22]4)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(C)(C)C)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: CC(C)(C)c1ccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)cc1

Procedure:
The title compound was prepared using the procedure of Example 1I, substituting the product of Example 3A for the product of Example 1H.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 509.0 [M+H]+; tR=3.07 min (System 1); Rf=0.10 (CH2Cl2/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[S:20][C:21]([C:24](O)=[O:25])=[CH:22][N:23]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:21]3[S:20][C:19]([Cl:18])=[N:23][CH:22]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1cnc(Cl)s1
Product: C[C@]1(c2cc(NC(=O)c3cnc(Cl)s3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 2-chloro-thiazole-5-carboxylic acid (CAS 101012-12-8) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=387.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ncnn2c(CCCCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 108 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (3.00 g, 5.70 mmol) in 95% aqueous ethanol (30 mL) was added concentrated hydrochloric acid (500 μL). The reaction was stirred (rt) for 1 h. The mixture was basified (pH 8) with the addition of saturated aqueous NaHCO3 solution and was evaporated to remove volatiles. The aqueous mixture was extracted with ethyl acetate (3×25 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated to afford 2.54 g (97%) of the desired product, which contained minor impurities. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.91 (s, 1 H), 7.82 (d, 1 H), 7.61 (s, 1 H), 7.40-7.29 (m, 5 H), 7.17 (dd, 1 H), 6.62 (s, 1 H), 5.68 (s, 2 H), 4.43 (t, 1 H), 3.46 (q, 2 H), 2.92 (t, 2 H), 1.82-1.71 (m, 2 H), 1.60-1.50 (m, 2 H); ES-MS m/z 413.4 [M+H]+, HPLC RT (min) 2.50.
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([CH:10](O)[CH3:11])[CH:9]=[C:4]2[CH:3]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[S:14][C:5]2=[N:6][C:7]([Cl:13])=[C:8]([CH:10]([N:19]3[C:15](=[O:25])[C:16]4[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:18]3=[O:20])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1cc2cc(Br)sc2nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2cc(Br)sc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a round-bottomed flask containing 1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethanol (2.0 g, 6.8 mmol), pthalimide (1.2 g, 8.2 mmol, 1.2 eq), and triphenylphosphine (2.15 g, 8.2 mmol) was added THF (45 mL). The solution was cooled to 0° C. and diisopropylazodicarboxylate (DIAD, 1.6 mL, 8.2 mmol, 1.2 eq) was added dropwise. The reaction was allowed to warm to room temperature. After 1 h, the reaction was judged to be complete by LC/MS. The solvent was removed in vacuo and the residue was redissolved in ether and washed with water. The water layer was back extracted with ether. The combined ether layers were washed with brine and dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography using 15% EA in hexanes to afford 2-(1-(2-bromo-6-chlorothieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. LC/MS (M+1, found=422.8). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.82 (m, 2H), 7.72 (m, 2H), 5.92 (q, J=7.0 Hz, 1H), 1.92 (d, J=7.0 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][C:14]([C:25]([NH2:27])=[O:26])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl-].[Ca+2].[Cl-].O>C(O)C.ClCCl.C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][CH:14]([C:25]([NH2:27])=[O:26])[NH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(C2=NN=C(C(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: Cc1cc(C2=NNC(C(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 25 h
Yield: 69 %

Procedure:
1.76 g (5.0 millimoles) of 5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carboxylic acid-amide are suspended in a mixture of 75 ml ethanol and 75 ml of dichloro methane, whereupon 0.19 g (5.0 millimoles) of sodium-[tetrahydrido-borate(IV)] are added in one portion and a solution of 0.55 g (5.0 millimoles) of calcium chloride in 25 ml of ethanol is added dropwise. The reaction mixture is stirred at room temperature for 25 hours and evaporated in vacuo. The residue is heated to boiling in 100 ml of water for half an hour and filtered hot. The crude product obtained is heated to boiling in 50 ml of acetonitrile for half an hour, cooled with icecold water, filtered and washed with 20 ml of diethyl ether. Thus 1.27 g of the desired compound are obtained, yield 69%, mp.: 246–249° C.