Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:23])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1

Procedure:
To a solution of 2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamine obtained by Example 53 (400 mg) and triethylamine (0.46 ml) in dichloromethane (20 ml) was added dropwise methanesulfonyl chloride (0.25 ml) at room temperature.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].I[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1>>[N+:15]([C:11]1[CH:10]=[C:9]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][C:2]2=[O:7])[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: O=C1CNCCN1
Reactant: O=[N+]([O-])c1cccc(I)c1
Product: O=C1CNCCN1c1cccc([N+](=O)[O-])c1

Procedure:
205 a) 1-(3-nitro-phenyl)-piperazin-2-one was prepared from piperazin-2-one (1.00 g, 9.99 mmol) and 1-iodo-3-nitro-benzene (3.00 g, 12.0 mmol) in a manner analogous to Example 204a. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.21 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 3.77 (t, J=4.9 Hz, 2H), 3.74 (s, 2H), 3.28 (t, J=4.8 Hz, 2H). MS=222 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.C1C(=O)N([I:18])C(=O)C1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[I:18][C:3]1[C:4]2[N:8]=[CH:7][NH:6][C:5]=2[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccc2[nH]cnc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]cnc2c1I
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A solution of 5-methyl-1H-benzoimidazole (132 mg, 1.0 mmol) and NIS (248 mg, 1.10 mmol) in 1 mL of TFA was reflux for 1 hr and then cooled to RT. Treated with 30 mL of EtOAc, the mixture was neutralized with sat. NaHCO3 solution. The organic layer was washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5% MeOH/CH2Cl2) gave 78 mg (30%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ 8.07 (d, 1H), 7.57 (br s, 1H), 7.22 (d, 1H, J. 8.4 Hz), 2.59 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C8H7IN2, 259.0 (M+H), found 259.2.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:8]1)(=O)=O.[CH2:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1)[CH3:17]>>[CH:13]1([CH2:12][N:9]2[CH2:10][CH2:11][CH:7]([CH2:6][N:18]([CH2:16][CH3:17])[C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:23][CH:24]=3)[CH2:8]2)[CH2:15][CH2:14]1
Reactant: CS(=O)(=O)OCC1CCN(CC2CC2)C1
Reactant: CCNc1ccc(-n2ccnc2)cc1
Product: CCN(CC1CCN(CC2CC2)C1)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-cyclopropylmethyl-3-pyrrolidinemethanol methanesulfonate with N-ethyl-4-(1H-imidazol-1-yl)benzenamine to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]([O-])=[CH:8][C:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=O)([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.[F:20][C:21]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][C:22]=1[C:23]#[N:24]>C(O)(=O)C>[C:23]([C:22]1[CH:25]=[C:26]([N:29]2[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[N:30]2)[CH:27]=[CH:28][C:21]=1[F:20])#[N:24]
Reactant: N#Cc1cc(NN)ccc1F
Reactant: CC(C)(C)OC(=O)C([O-])=CC(=O)c1ccco1
Agent: Cl
Agent: [Li+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1cc(-c2ccco2)n(-c2ccc(F)c(C#N)c2)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
Part A. To lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (13 g, 54 mmol; Example 74, Part A) was added 2-fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250 mL of glacial acetic acid. The resulting orange mixture was maintained at rt for 20 h and then concentrated to dryness. The resulting residue was taken up in 30% chloroform in hexanes and filtered to afford tert-butyl 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate (18 g, 95%) as a light brown solid. LC/MS (ESI+): 354.2 (M+H)+. 1H NMR (CDCl3) δ 7.64-7.78 (m, 3H), 7.42 (s, 1H), 7.05 (s, 1H), 6.45 (s, 1H), 6.30 (s, 1H), 1.61 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(#N)C>[C:1]1([CH2:7][CH2:8][C:9]2[NH:17][C:12]3=[N+:13]([O-:26])[CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCc2cc3cccnc3[nH]2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Product: [O-][n+]1cccc2cc(CCc3ccccc3)[nH]c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.4 %

Procedure:
To a solution of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine (1.97 g, 8.86 mmol) in acetonitrile (100 mL) was added m-chloroperbenzoic acid (2.82 g, 10.63 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) to give the title compound (1.17 g, yield 55%) as a yellow amorphous form.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[C:21]([CH3:31])[CH:20]=1>>[CH3:17][O:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22](/[CH:23]=[CH:24]/[C:25]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[C:21]([CH3:31])[CH:20]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(C)c(OC)cc3C)nc2n(CCC)c1=O
Yield: 45 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.5 g (11.1 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.51 g (12.17 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.98 g (yield 45%) of Compound 45 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:29][CH2:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: NCCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCCO)ccc21
Yield: 65.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (3-hydroxy-propyl)-amide (136 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (179 mg), 3-amino-propan-1-ol (40 mg), HBTU (209 mg), and DIEA (200 uL) in DMF (1 mL). LC/MS: m/z 415.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:22])=[O:21])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:22])=[O:21])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:29]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C1Nc2ccc(Cl)cc2[C@](CCCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1

Procedure:
N-{3-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]propyl}pyridine-2-sulfonamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:2), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:9]=1[C:10]#[N:11].Cl[C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:23]2[CH:24]=[C:25]3[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]3[C:27](=[O:29])[N:28]=2)=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(Cl)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 2-(3-chloro-4-fluorophenoxy)-5-(hydroxymethy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1 (5H)-carboxylate.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Reactant: NCCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH+:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:10])=[CH:7][CH:6]=1)([OH:4])=O.[Br:31][C:32]1[C:40]2OC(C3C=CC(C([O-])=O)=CC=3)=[N:37][C:36]=2[CH:35]=[C:34]([C:50]#[N:51])[CH:33]=1>>[Br:31][C:32]1[C:40]2[O:4][C:2]([C:5]3[CH:30]=[CH:29][C:8]([C:9]([NH:11][CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]5[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=5)[CH2:15][CH2:14]4)=[O:10])=[CH:7][CH:6]=3)=[N:37][C:36]=2[CH:35]=[C:34]([C:50]#[N:51])[CH:33]=1
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)[O-])cc3)nc2c1
Reactant: O=C(O)c1ccc(C(=O)NCC2CC[NH+](c3ccc(C(F)(F)F)cn3)CC2)cc1
Agent: [Cl-]
Product: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-{[(4-carboxybenzoyl)amino]methyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidinium chloride and 3-amino-5-bromo-4-hydroxybenzonitrile (INTERMEDIATE 1, Step B) by a procedure analogous to that described in EXAMPLE 109. Mass spectrum (ESI) 585.9 (M+3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(SCCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1
Reaction time: 1 h

Procedure:
2-((3-Methyl-4-(3-benzylaminopropylthio)-2-pyridyl)methylthio)-1H-benzimidazole (2.0 g) was dissolved in dimethylformamide (25 ml) and thereto were added ethyl bromoacetate (0.834 g) and potassium carbonate (0.984 g). The mixture was stirred at 40°-50° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to column chromatography and eluted with chloroform-methanol to give 2-((3-methyl-4-(3-(N-benzyl-N-ethoxycarbonylmethylamino)propylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=1.[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1>>[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH2:2][C:3]2[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=2)[N:13]=[C:12]([OH:17])[CH:11]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cnc(CCl)c1
Product: Cc1cc(O)nc(SCc2cn(C)cn2)n1
Yield: 60 %

Procedure:
This example was synthesized from 4-(chloromethyl)-1-methyl-1H-imidazole and 6-methyl-2-sulfanylpyrimidin-4-ol following the general procedure as shown in the last step of Example 109. This provided the title compound as a white solid (260 mg, 60% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.60 (s, 3H), 4.24 (s, 2H), 5.97 (bs, 1H), 7.06 (s, 1H), 7.52 (s, 1H); M+ 237.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Product: CCC(=O)NC1CCCc2c(-c3ccc(F)c(Cl)c3)cncc21
Yield: 74 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 3-chloro-4-fluorophenylboronic acid to give the title compound as light grey foam in 74% yield. MS: 333.1 (M+H+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:27][C:24]2[CH:25]=[N:26][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CC(C)N1CCN(c2ccc(N)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cn2)CC1
Temperature: 90 °C
Reaction time: 48 h
Yield: 71.3 %

Procedure:
To a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.85 g, 3.1 mmol) in isopropanol are added 6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl-amine (0.68 g, 3.1 mmol) and diisopropylethylamine (0.6 mL, 4.6 mmol) and the mixture is stirred at 90° C. for 48 hours. The solvent is removed in vacuo and the product taken up in DCM-10% citric acid. The organic layer is discarded and the aqueous solution basified with sat. NaHCO3 (pH 7-8) and extracted using DCM. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a purple solid (0.92 g, 71%). HPLC (254 nm): Rt 3.30 min (95.8%); m/z 416/418 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 30 g (0.217 mol) 6-hydroxy-nicotinic acid in 50 ml concentrated sulfuric acid was added 60 ml of a 1:1 mixture of conc. sulfuric acid and conc. nitric acid below 20° C. and stirred for 1 h at room temperature and afterwards heated to 80° C. for 4 h. The mixture was poured onto ice and the formed precipitate was collected and dried to yield 14.2 g (36%) of the title compound as a yellow amorphous solid.
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Br:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:9][O:10][N:11]=1.[S:26](N)([NH2:29])(=[O:28])=[O:27]>N1C=CC=CC=1>[Br:24][C:19]1[CH:18]=[C:17]([N:16]2[C:15](=[O:25])[O:14][N:13]=[C:12]2[C:8]2[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:26]([NH2:29])(=[O:28])=[O:27])=[N:11][O:10][N:9]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: NS(N)(=O)=O
Agent: I
Solvent: c1ccncc1
Product: NS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Yield: 71.7 %

Procedure:
A solution of 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydroiodide (150 mg, 0.28 mmol) and sulfamide (160 mg, 1.7 mmol) in pyridine (2.5 mL) was heated in a microwave at 130° C. for 10 min. The reaction mixture was concentrated to give a crude residue. This material was purified by preparative LCMS to give the desired product (96 mg, 71%) as a solid. LCMS for C13H14BrFN7O5S (M+H)+: m/z=478.0, 480.0. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (dd, J=6.2, 2.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.59 (dd, J=8.8, 8.6 Hz, 1H), 6.57-6.51 (m, 4H), 3.31-3.26 (m, 2H), 2.92-2.87 (m, 2H), 1.79-1.72 (m, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:61][CH2:60][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34].[CH3:62][O:63][CH:64]([O:72][CH3:73])[CH2:65][NH:66][CH2:67][C:68]([F:71])([F:70])[F:69].C(N(CC)CC)C>CN(C=O)C>[CH3:73][O:72][CH:64]([O:63][CH3:62])[CH2:65][N:66]([CH2:67][C:68]([F:69])([F:70])[F:71])[C:33](=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]1[CH:36]=[CH:37][CH:38]=[C:39]([CH2:40][N:41]2[CH2:42][CH2:43][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:60][CH2:61]2)[C:26]=1[F:25]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Reactant: COC(CNCC(F)(F)F)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(CN(CC(F)(F)F)C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1F)OC
Temperature: 20 °C
Reaction time: 72 h

Procedure:
HATU (0.30 g) was added in one portion to a cooled solution (ice bath) of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 7, step d] (0.32 g) and N-(2,2-dimethoxyethyl)-2,2,2-trifluoroethanamine [Amine 14] (0.17 g) and triethylamine (0.25 mL) in DMF (7 mL). The mixture was stirred at 20° C. for 3 days, then partitioned between ethyl acetate and brine. The organic phase was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, using 5% methanol in ethyl acetate with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.15 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1CC(NC(=O)c1cc(OC)c2ccccc2n1)C(=O)N1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.6 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-hydroxyphenyl)ethyl]aminocarbonyl-4-methoxyquinoline (200 mg, 0.39 mmol) in DMF (5 mL) was added CsCO3 (260 mg, 0.8 mmol) and ethyl bromoacetate (120 mg, 0.7 mmol) and the reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was partitioned in water and ethyl acetate and extracted with ethyl acetate. Combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-(ethoxycarbonyl)methoxyphenyl)ethyl]aminocarbonyl-4-methoxyquinoline as a white solid 140 mg (60%); NMR (DMSO-d6), 1.18 (m, 6), 3.26 (m, 10), 4.00 (q, 2), 4.04 (s, 3), 4.84 (s, 2), 5.26 (m, 1), 6.82 (q, 1), 7.88 (d, 1), 7.48 (s, 1), 7.64 (t, 1), 7.82 (t, 1), 8.06 (d, 1), 8.16 (d, 1), 8.86 (d, 1) ppm.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])[N:5]=[C:4]1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:2].[C:26]1(=O)[CH2:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH:26]1([N:13]2[CH2:12][CH2:11][CH:10]([CH:8]([C:6]3[N:5]=[C:4]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)[N:3]([CH2:1][CH3:2])[CH:7]=3)[OH:9])[CH2:15][CH2:14]2)[CH2:29][CH2:28][CH2:27]1
Reactant: O=C1CCC1
Reactant: CCn1cc(C(O)C2CCNCC2)nc1-c1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1cc(C(O)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-ethyl-2-naphthalen-1-yl-1H-imidazol-4-yl)-piperidin-4-yl-methanol (0.53 g) in CH2ClCH2Cl (12 ml) is added cyclobutanone (0.95 ml), followed by NaBH(OAc)3 and acetic acid (0.1 ml). The resulting mixture is stirred at rt overnight, diluted with CH2Cl2, washed with Na2CO3 (1M), H2O and brine, dried and solvent removed. The crude is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as a white solid, LCMS 390.1 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(C(C)(C)C)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (72 mg, 81%), MS (ISP) m/z=358.5 [(M+H)+], mp 292° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).