Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH:21](=[O:23])[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:21]([OH:23])[CH3:22]
Reactant: CC=O
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)c1c(F)cncc1Br
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
n-BuLi (1.6M in hexanes) (19.60 ml, 31.4 mmol) was added dropwise to a solution of diisopropylamine (4.84 ml, 34.0 mmol) in THF (87 ml) at −78° C. under N2. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recoiled to −78° C. 3-bromo-5-fluoropyridine (4.6 g, 26.1 mmol) in 5 mL THF was added dropwise at this temperature. After 30 min, acetaldehyde (2.95 ml, 52.3 mmol) was added dropwise and the resulting mixture was stirred for 30 min at −78° C., and then for another 30 min at 0° C. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (SNAP50, 0-30% AcOEt/heptane, v/v) giving the title compound 4a (2.869 g, 50%) as yellow oil. LC-MS (M+1) 221.9, t=1.01 min.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([Br:36])[CH:35]=1)[CH2:7][O:8][C@H:9]1[C@H:18]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1.[CH3:37]I>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([Br:36])[CH:35]=1)[CH2:7][O:8][C@H:9]1[C@H:18]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]([CH3:37])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:23][CH2:24]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCN([C@@H]2c3ccccc3OC[C@H]2OCc2cc(Br)cc(Br)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN([C@@H]2c3ccccc3OC[C@H]2OCc2cc(Br)cc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.2 g of sodium hydride (60% in oil) is added to 1 g of the compound obtained in Step B of Example 9 and 0.42 ml of methyl iodide in 10 ml of tetrahydrofuran, maintaining the temperature of the reaction mixture at 0° C. After 15 minutes at that temperature, the mixture is stirred for 48 hours at ambient temperature, diluted with water and extracted with ethyl acetate. After conventional treatment, the expected product is isolated.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[N:22]([C@@H:26]([CH3:29])[CH2:27][OH:28])[CH2:21]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.O[C:52]1[CH:84]=[CH:83][C:55]([CH2:56][CH:57]2[S:61][C:60](=[O:62])[N:59]([C:63]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]2=[O:82])=[CH:54][CH:53]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[N:22]([C@@H:26]([CH3:29])[CH2:27][O:28][C:52]2[CH:84]=[CH:83][C:55]([CH2:56][CH:57]3[S:61][C:60](=[O:62])[N:59]([C:63]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)([C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=4)[C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[C:58]3=[O:82])=[CH:54][CH:53]=2)[CH2:21]1
Reactant: C[C@@H](CO)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 29 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 405 mg of tributylphosphine, 25 ml of anhydrous benzene, 700 mg of 2(S)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propanol (prepared as described in Preparation 40), 505 mg of azodicarbonyldipiperidine and 745 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione were used, to give 340 mg of the title compound, melting at 80° C. to 84° C. and having [α]D =+25.9° (methanol, c=0.96).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC>CN(C=O)C.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>[CH2:33]([O:32][C:30]([C:2]1[N:7]=[C:6]2[N:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:31])[CH3:34]
Reactant: CC(c1c(F)cc2ncccc2c1F)n1nnc2ncc(Br)nc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A mixture of 6-(1-(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline (423.0 mg, 1.2 mmol), Pd(Ph3P)4 (125.0 mg, 0.12 mmol) and tributyl(1-ethoxyvinyl)stannane (781.0 mg, 2.2 mmol) in DMF (5 mL) was purged with nitrogen and then heated at 100° C. for 12 hours. After removal of the solvent under reduced pressure, the residue was diluted with DCM, washed sequentially with aqueous KF and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with gradient (DCM/MeOH=50:1) to give the title compound as a yellow solid (370 mg, 91%). LCMS (method E): [MH]+=383, tR=4.24 min.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:27].CC(O)=O>CN(C=O)C>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:27]
Reactant: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NCSC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
BocCys(Acm)ONp is prepared from BocCys(Acm)OH (Novabiochem, Laufalingen, CH) and p-nitrophenol by reaction with N,N'-dicyclohexylcarbodiimide (DCC) in ethyl acetate and used without purification for the preparation of Boc-Cys(Acm)-Pro-OH (XII) by reacting it with H-Pro-OH in DMF/etyl acetate/HCl at 0° C. while keeping pH neutral by addition of Et3N. Yield 81%. Purity>95% (TLC). Boc-Asn-Cys(Acm)-Pro-OH (XIII) is obtained by deblocking XII in HCl/HOAc at room temperature, dissolving the thus obtained raw H-Cys(Acm)-Pro-OH.HCl in DMF and neutralizing it with Et3N, and adding Boc-Asn-ONp (Novabiochem, Laufelingen, CH) at -5° C. while keeping pH neutral. XIII is isolated in 81% yield. [a]D20 =-77.1° (1 g/100 ml DMF). The tetrapeptide derivative X is prepared from XIII and Boc-Gln-ONp (Novabiochem, Laufelingen, CH) in a way corresponding to the preparation of XIII from XII and Boc-Asn-ONp. Yield 78.5%; [a]D20 =-89.7° (1 g/100 ml H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9](O)O)[CH:5]=[CH:6][C:7]=1[F:8].[C:12]1([NH2:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:22])[CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]2[NH:23][C:12]3[C:21]4[C:16]([CH:15]=[CH:14][CH:13]=3)=[CH:17][CH:18]=[CH:19][C:20]=4[NH:22]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cccc2cccc(N)c12
Reactant: OB(O)c1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Product: Fc1ccc(B2Nc3cccc4cccc(c34)N2)cc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 3-chloro-4-fluorobenzene boronic acid (4 g, 22.8 mmol) and naphthalene-1,8-diamine (3.62 g, 22.9 mol) in anhydrous toluene (80 mL) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, then concentrated in vacuo. The residue was trituated with hexane to afford the title compound as a grey solid in 88% yield, 6 g.
Reaction SMILES: C1S(=O)(=O)CCC1.Cl[C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][N:10]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH2:19].N>C(Cl)Cl>[Cl:15][C:13]1[CH:14]=[C:9]([NH:19][C:18]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:17]=2[Cl:16])[N:10]=[CH:11][N:12]=1
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: Clc1cc(Cl)ncn1
Agent: N
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc(Cl)c(Nc2cc(Cl)ncn2)c1
Temperature: 125 °C
Yield: 57.4 %

Procedure:
Tetramethylene sulphone (10 ml) was added to 4,6-dichloropyrimidine (25.0 g, 170 mmol) and heated to 125° C. 2-Chloro-5-methylaniline (11.90 g, 84 mmol) was added portion wise over 20 mins. The reaction mixture was heated at 125° C. for 2 hours. The reaction was allowed to cool to room temperature and DCM (200 ml) was added. The mixture was basified to pH 9-10 with methanolic ammonia and evaporated onto silica (15 g). The residue was purified by column chromatography eluting with EtOAc:isohexane (10:90) to give a white solid (12.25 g, 29%). NMR (300 MHz): 2.3 (s, 3H), 6.7 (s, 1H), 7.0 (d, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 8.4 (s, 1H), 9.4 (s, 1H); m/z 254 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#[CH:24].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[C:23][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#Cc1ccccn1
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#Cc3ccccn3)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 2-ethynylpyridine under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The fractions homogenous by TLC were combined and evaporated. Crystallization of the residue from ethyl acetate and recrystallization from tetrahydrofuran/methanol gave off-white crystals of 4-(2-chlorophenyl)-9-methyl-2-[2-(2-pyridinyl)-ethynyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with m.p. 153°-155°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:21](=[O:24])[CH2:22][CH3:23])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 95.4 %

Procedure:
400 mg (2 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide (Example 1b) are dissolved in 15 ml dichloromethane, cooled in the ice-bath and treated with 0.36 ml triethylamine. 185 mg (2 mmol) propionyl chloride are added dropwise with ice cooling. The mixture is stirred for 30 minutes in the ice-bath and for 15 hours at room temperature. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 489 mg (96%) of the desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([OH:22])=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (7.53 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate were dissolved in 18 ml of tert-butanol, and 5 ml of water were then added. After cooling to 0° C., 2.35 g (15.1 mmol) sodium dihydrogenphosphate dihydrate, 2.73 g (30.1 mmol) of sodium chlorite and 3.17 g (45.2 mmol) of 2-methyl-2-butene were added in succession. After 1 hour at 20° C., water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure (logP: 1.38)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][OH:5].C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzyl alcohol (2.216 g, 8.69 mmol) and N-methylmorpholine-N-oxide (2.051 g, 17.38 mmol) were combined in CH2Cl2 (44 mL) and MeCN (2.2 mL). Tetrapropylammonium perruthenate (0.311 g, 0.87 mmol) was added, and the reaction was stirred for 20 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: N1C=CC=CC=1P([CH2:14][P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)C1C=CC=CC=1.ClCCl>ClCCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH2:14][P:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(P(CP(c2ccccc2)c2ccccn2)c2ccccn2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: c1ccc(P(CCP(c2ccccc2)c2ccccn2)c2ccccn2)cc1

Procedure:
An amount of 1,2-bis[(2-pyridyl)(phenyl)phosphino]ethane was prepared substantially in the same way as the diphosphine of Example 2, except that, instead of dichloromethane, 1,2-dichloroethane was employed.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:27][NH:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:29][CH:28]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Yield: 93 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added 4-phenoxybenzohydrazide. After stirring at 100 ° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 4940 mg of the title compound (93%) as a yellow solid in 99.9% purity by HPLC (Rt: 5.13, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2].[C:18]([O-])(=[O:20])C.[Na+].C(O)(=O)C.C=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH2:18][OH:20])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc(C2CCc3nccn32)cc1F
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C2CCc3ncc(CO)n32)cc1F

Procedure:
A solution of product from Step H (3.79 g, 16.7 mmol), sodium acetate (2.44 g, 29.7 mmol), acetic acid (1.82 mL, 31.9 mmol), and formaldehyde (37% in water, 15.1 mL) was heated to reflux for 96 hours. The reaction was slowly neutralized by the addition of sat. aq. NAHCO3. The aqueous layer was extracted with methylene chloride (5×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (1→10% MeOH/CHCl3) to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([C:24]([NH2:26])=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][C:11](=[O:13])[OH:12])=[O:7])[CH2:3][CH2:4][CH3:5].Cl.[NH:28]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:29]([C:40](ON1C(=O)CCC1=O)=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[NH:28]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:29]([C:40]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([C:24]([NH2:26])=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][C:11](=[O:12])[OH:13])=[O:7])[CH2:3][CH2:4][CH3:5])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Reactant: CCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 63.3 %

Procedure:
1.50 g (3.74 mmoles) of H-Nva-Asp-D-Phg-NH2.HCl are reacted with 1.50 g (3.74 mmoles) of BOC-Trp-OSu in 30 ml of DMF in the presence of 1.05 ml (7.5 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the residue is admixed with water, and the mixture is filtered. The obtained crude product, weighing 2.36 g, is recrystallized from 300 ml of 80% ethanol. 1.54 g (66.2%) of BOC-Trp-Nva-Asp-D-Phg-NH2 are obtained; m.p.: 240° C. (decomposition), Rf5 :0.35, [α]D :-60.5° (c: 1.0, in dimethyl formamide).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([NH:9][C:10](=[O:17])[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][CH:8]=1)#[CH:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29](I)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.N1CCCCC1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:2]#[C:1][C:3]3[CH:4]=[C:5]([CH3:18])[C:6]([NH:9][C:10](=[O:17])[CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:7][CH:8]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Reactant: C#Cc1cnc(NC(=O)CN2CCCC2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cnc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 4 mg (0.01 mmol) Pd(PPh3)2Cl2 and 1 mg (0.01 mmol) CuI are added to a solution of 73 mg (0.3 mmol) N-(5-ethynyl-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide and 95 mg (0.3 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 59 μL (0.6 mmol) piperidine and 10 mL THF and the reaction mixture is stirred for 30 min at RT. It is evaporated down i.vac., the residue is taken up in EtOAc, the organic phase is washed with water and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified first by chromatography (silica gel, EtOAc/MeOH/NH3 95:5:0.5) and then by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7](=[O:19])[CH2:8][C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH2:27]([O:29][C:30](=[O:33])[CH2:31]Cl)[CH3:28].[H-].[Na+]>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:33])[CH2:31][CH:8]1[C:7](=[O:19])[N:6]([CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]1=[O:18])[CH3:28]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)CN1C(=O)CC(=O)N(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1C(=O)N(CC(C)(C)C)c2ccc(Cl)cc2N(c2ccccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-5-(2-chlorophenyl)-2,4-dioxo-1-neopentyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.3 g) and chloroacetic acid ethyl ester (0.11 ml) in dimethylformamide (2 ml) was added sodium hydride (60% oil, 40 mg), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture were further added sodium hydride (40 mg×3) and chloroacetic acid ethyl ester (0.11 ml), which was stirred for 3 hours. To the mixture was then added acetic acid ethyl ester (50 ml), which was washed with water. The solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=4:1 v/v as an eluent) to give 0.25 g of colorless crystals, m.p. 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[C:27]#[N:28]>>[C:27]([C:26]([NH:25][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=12)=[O:23])([CH3:30])[CH3:29])#[N:28]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CC(C)(N)C#N
Product: CC(C)(C#N)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 57 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and 2-amino-2-methylpropanenitrile to yield the title compound as a white solid (21 mg, 57% yield). MS (apci) m/z=394.1 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O-:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[NH:23][C:19]=2[CH:18]=1>>[O:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:22]4[NH:21][C:20]5[CH:44]=[CH:45][C:17]([NH:16][C:11](=[O:13])[C:10]6[CH:9]=[CH:8][C:7]([N:4]7[CH2:3][CH2:2][O:1][CH2:6][CH2:5]7)=[CH:15][CH:14]=6)=[CH:18][C:19]=5[N:23]=4)=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)[CH2:39][CH2:40]1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc2nc(-c3ccc(N4CCC(CCN5CCOCC5)CC4)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCC(CCN5CCOCC5)CC4)cc3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 446 was prepared from 4-morpholinobenzoate and 5-amino-2-(4-(4-(2-morpholinoethyl)piperidino)phenyl)benzimidazole by standard conditions. [M+H]+ calcd for: C35H42N6O3; 595.33 found: 595.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](C1C=CC=CC=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[CH2:7]([C:8]1[N:9]=[N:10][C:11]2[C:6]([C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[Cl:25])[CH:19]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Clc1ccccc1CBr
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1ccccc1COc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenol and 2-chlorobenzyl bromide according the procedure of Example 14. MS (ES) m/z 470.8.