Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13](F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([NH2:34])[CH2:31][CH2:32][NH2:33]>>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][NH2:34])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: NCCCN
Product: COc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro-6-methoxyquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methoxyquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 8.01-7.99 (d, J=8 Hz, 1 H), 7.83-7.81 (d, J=7.2 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.52-7.50 (d, J=7.6 Hz, 2 H), 7.30-7.27 (d, J=9.2 Hz, 1 H), 5.90 (s, 1 H), 5.25 (s, 2 H), 4.46 (s, 2 H), 3.83 (s, 3 H), 3.66 (s, 2 H), 3.56 (s, 2 H), 3.08-3.07 (t, J=7.2 Hz, 2 H), 2.09-2.06 (d, J=5.2 Hz, 2 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH:26][C:27]3[N:28]=[C:29]([Br:32])[S:30][CH:31]=3)=[O:25])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:29]1[S:30][CH:31]=[C:27]([NH:26][C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:18]=2)=[O:25])[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cccc(NC(=O)Nc3csc(Br)n3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(OCCC2CCNCC2)n1)Nc1csc(Br)n1

Procedure:
To a stirred solution of 4-(2-{6-[3-(2-bromo-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (285 mg, 0.54 mmol) in anhydrous CH2Cl2 (6 mL) at RT, under N2, TFA (1.5 mL) was added. After 1.5 h the solvent was evaporated in vacuo. The residue was carefully treated with a saturated solution of NaHCO3 (aq) (10 mL), the precipitate was filtered off, washed with Et2O (3×5 mL) and dried in a vacuum oven at 60° C. for 5 h to yield the title compound as a white amorphous solid. MS m/z: 426.2, 428.2 (M+H). Calc'd. for C16H20BrN5O2S-426.33.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.N(OC(C)(C)C)=O.[ClH:25].CO>C(#N)C.[Cu](Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: Cl
Reactant: N#Cc1ccc(-c2cc(N)cc(CO)c2)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CO
Product: N#Cc1ccc(-c2cc(Cl)cc(CO)c2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 3′-amino-5′-(hydroxymethyl)biphenyl-4-carbonitrile (120 mg, 0.54 mmol) in dry acetonitrile (1 mL) was added dropwise to a solution of copper (II) chloride (86 mg, 0.64 mmol) and tert-butyl nitrite (91 μL, 0.78 mmol) in acetonitrile (2 mL) at 65° C. After stirring for 30 min at 65° C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) afforded 46 mg (35%). LC/MS: tR=2.54 min, 244.03 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: [C:1]([C:3]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].C(N(C(C)C)CC)(C)C.[ClH:37].[N:38]1([C:43](N)=[NH:44])C=CC=N1>CN(C)C=O>[ClH:37].[ClH:37].[C:1]([C:3]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][N:24]([C:43]([NH2:44])=[NH:38])[CH2:25]3)=[CH:20][CH:19]=2)[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(CCOc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(CCOc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.7 %

Procedure:
To a solution of 7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline (70 mg) in dimethylformamide (5 ml)solution were added diisopropylethylamine (0.1 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (85 mg), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by HPLC (0.05% aquesous trifluoroacetic acid:methanol=1:1). The obtained residue was treated with dil. hydrochloric acid and dried under reduced pressure to give the title compound (67 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[N:25]=[CH:24][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:22]=4)[CH:19]=3)[N:14](C3CCCCO3)[N:13]=2)[CH:7]=1)(=[O:4])=[O:3]>O1CCOCC1.Cl>[NH:23]1[CH:24]=[N:25][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=[CH:10][CH:9]=2)=[N:22]1
Reactant: CS(=O)(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 18 h
Yield: 71 %

Procedure:
Hydrolysis was performed by stirring (methylsulfonyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)amine (0.140 g, 0.205 mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 18 hours. The title compound was purified by preparative HPLC (15–80% acetonitrile in water) (0.052 g, 71% yield): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.0 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.1 (d, 1H), 7.9 (s, 1H), 7.7 (dd, 2H), 7.5 (dd, 1H), 7.3 (d, 1H), 3.06 (s, 3H); ES-MS (m/z) 355 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH:37][CH3:38]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:37]([CH3:38])[CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (730 mg, 1.44 mmol) and N,N-dimethylamine (2M in THF) (800 μl, 1.60 mmol) as starting materials.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:17]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([CH:21]1[CH2:22][CH2:23][CH:24]([C:27]([NH:1][CH:2]([C:5]2[C:6](=[O:16])[NH:7][C:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:28])[CH2:25][CH2:26]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)C1CCC(C(=O)Cl)CC1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 200 mg (0.90 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 180 mg (0.90 mmol) 4-tert-butylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22](=O)[C:23]#[C:24][CH2:25][O:26]C)C>C(O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:25](=[O:26])[CH:24]=[C:23]([CH2:22][O:21][CH3:19])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: CCOC(=O)C#CCOC
Solvent: CCO
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)C)cc1)O2
Yield: 69.6 %

Procedure:
To a solution of (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine (2.3 g, 9.26 mmol) (prepared according to the procedures employed in Step 1 through 2 of Example 1) in ethanol (35 mL) was added 1.7 g (12.04 mmol) of 4-methoxy-but-2-ynoic acid ethyl ester (prepared in accordance with the procedures as described in Larock, J Org Chem 2002, 67, 9318). This mixture was stirred at reflux for 6 hours and cooled. The reaction mixture was concentrated and loaded onto a silica gel column. Chromatography with 1-10% EtOH/CH2Cl2 provided 2.22 g of the title compound. [α]D25 −18.00 (c 0.5, CHCl3)
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[CH3:11])=[O:7])=[C:4]([F:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[CH3:11])=[O:7])=[C:4]([F:26])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(CNC(=O)c1ccc(Br)cc1F)c1ccc(CN2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)cc1F)c1ccc(CN2CCCC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution (7 ml) of 4-bromo-2-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}benzamide (300 mg, 0.715 mmol) obtained in Example 5, 4-chlorophenylboronic acid (224 mg, 1.43 mmol) and 2N aqueous sodium carbonate solution (0.715 ml) in tetrahydrofuran was added tetrakistriphenylphosphine palladium (24.8 mg, 21.5 mmol) under a nitrogen atmosphere. This was stirred at 90° C. for 16 hrs, and allowed to cool to room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate), and powderized with isopropyl ether to give the title compound (142 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[CH2:11]([NH:18][CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:11]([N:18]([CH2:19][CH2:20][OH:21])[CH2:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCNCc1ccccc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN(Cc1ccccc1)Cc1ccc(Cl)c(Cl)c1
Yield: 57.5 %

Procedure:
To a solution of 13 g of 3,4-dichlorobenzyl chloride and 9.15 g of N-benzylethanolamine in 150 ml of dimethylformamide (DMF), 9 g of anhydrous potassium carbonate was added and the mixture was vigorously stirred. After stirring for 24 hours, the reaction mixture was acidified by adding 10% HCl and extracted with isopropyl ether. The aqueous phase was made basic with 10% sodium hydroxide solution and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to produce the object compound (10.8 g, yield 57%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]([C:20]1[S:35][C:23]2[N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25](=[O:28])[CH:26]=[CH:27][C:22]=2[C:21]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C(=O)OC(C)(C)C)(=[O:11])=[O:10].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:28]=[C:25]1[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[S:35][C:20]([NH:12][S:9]([CH3:8])(=[O:11])=[O:10])=[C:21]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:22]=2[CH:27]=[CH:26]1
Reactant: CC(C)(C)OC(=O)N(c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of the compound of Example 82 (105 mg, 0.212 mmol) in DCM (2.5 mL) and the reaction mixture stirred for 2 h at r.t. The mixture was added to saturated NaHCO3 solution (20 mL) and the product extracted with DCM (2×20 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by radial chromatography on silica (EtOAc) to give the title compound (62 mg, 74%). δH (CDCl3) 7.6–7.25 (11H, m), 6.58 (1H, d, J 9 Hz), 6.31 (1H, br s), 2.53 (3H, s). m/z (ES+) 397 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:21]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[CH:24][CH:23]=1)#[N:20]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(Oc2ccccc2)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
(RS)-Methoxy-(4-phenoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(4-phenoxy-phenyl)-acetamide. Colorless solid. MS 373.3 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:33])[CH3:35]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CCCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded butyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:30][O:31][C:32](=[O:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39](=O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH3:30][O:31][C:32](=[O:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39](=[CH:2][O:3][CH3:4])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:34]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCC(=O)c1ccc(C(=O)OC)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCC(=COC)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (10.34 g, 30.24 mmol) is suspended in anhydrous toluene (75 mL) and potassium tert-butoxide (3.39 g, 30.24 mmol) is carefully added. The solution is allowed to stir at room temperature for 4 h. 4-Heptanoyl-benzoic acid methyl ester (5.0 g, 20.16 mmol) is then dissolved in anhydrous toluene (25 mL) and added to the reaction mixture by cannula. The reaction is allowed to stir at room temperature overnight and is monitored by TLC. Upon complete consumption of starting material, the reaction is carefully quenched with saturated ammonium chloride solution, extracted with diethyl ether, washed, dried, and concentrated. The title compound is purified by column chromatography using hexanes/ethyl acetate and used directly in the next step.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.[CH:10]1[N:14]2[C:15]3[C:20]([N:21]=[CH:22][C:13]2=[N:12][C:11]=1[CH:23]=O)=[CH:19][CH:18]=[CH:17][CH:16]=3>C(O)C>[CH:10]1[N:14]2[C:15]3[C:20]([N:21]=[CH:22][C:13]2=[N:12][C:11]=1[CH:23]=[N:2][OH:3])=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=Cc1cn2c(cnc3ccccc32)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1cn2c(cnc3ccccc32)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A solution of 1.4 g of hydroxylamine hydrochloride, 1.9 g of sodium acetate and 5 ml of water was added to a suspension of 3.10 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde in 30 ml of ethanol and the mixture was stirred at 90° C. for 4 hours and was evaporated to dryness. The white crystalline residue was triturated with water and was filtered. The product was dried in vacuo over phosphorus pentoxide to obtain 2.83 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime melting at 243°-245° C.
Reaction SMILES: [C:1]([N:11]1[CH2:13][C:12]1([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:16]([CH:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[OH:21])([CH3:19])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][C:12]([CH3:14])([CH3:15])[CH2:13][O:21][CH:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:16]([CH3:19])([CH3:18])[CH3:17])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)C(O)C(C)(C)C
Reactant: CC1(C)CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2,2-Dimethyl aziridine and di-t-butylmethanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-2-amino-2-methyl-1-[di-(t-butyl)-methoxy]propane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[N:10]=3)[CH:23]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-difluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.78) (0.15 g, 0.33 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.103 g, 0.4 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.16 g) which was subsequently deprotected.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[CH2:15](O)[CH2:16][OH:17].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([C:12]1[C:6]2[O:5][C:4]([C:1]3([CH3:2])[O:17][CH2:16][CH2:15][O:3]3)=[CH:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)[CH3:14]
Reactant: CCc1cccc2cc(C(C)=O)oc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cccc2cc(C3(C)OCCO3)oc12
Yield: 78.8 %

Procedure:
A stirred mixture of 50 g of 2-acetyl-7-ethylbenzofuran, 3.0 g of paratoluenesulphonic acid and 45.0 g of ethyleneglycol in 1200 ml of toluene was heated under reflux for 12 hours with azeotropic removal of water. The cooled solution was washed successively with dilute sodium hydroxide solution, water and brine and then dried over anhydrous sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated to dryness. The residual yellow oil was distilled under nitrogen to give 48.6 g of 7-ethyl-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran of boiling point 86°-88°C/0.05 mm Hg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Yield: 78 %

Procedure:
Compound A2 (0.12 mmol, 50 mg), 3,3-dimethyl-butyryl chloride (0.18 mmol, 24 mg) and triethylamine (0.63 mmol, 88 L) were dissolved in DMF and microwaved at 80° C. for 5 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvents in vacuo provided Compound A3 as a yellow solid (46 mg, 78%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.98 (s, 1H), 8.20 (s, 1H), 7.77 (d, 2H), 7.64 (d, 2H), 5.44 (heptet, 1H), 3.71 (m, 1H), 3.48 (m, 3H), 2.75 (s, 3H), 2.11 (quartet, 2H), 1.76 (m, 4H), 0.85 (s, 9H). LCMS (ESI), m/z 492.4 (M+H+, 100%).