Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].O1CCCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC(C#N)Cc1ccc(Cl)cc1Cl
Yield: 68.9 %

Procedure:
Using 4.46 g of (2,4-dichlorobenzylidene)malononitrile, 20 ml of tetrahydrofuran, and a suspension of 0.19 g of sodium borohydride in 5 ml of ethanol, and according to the process described in Reference Production Example 8, there was obtained 3.10 g of (2,4-dichlorobenzyl)malononitrile (the intermediate (13)).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([O:11][CH:12]([O:25][CH2:26][CH3:27])[CH2:13][N:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=[O:16])[CH3:10]>O.C(O)C>[CH2:9]([O:11][CH:12]([O:25][CH2:26][CH3:27])[CH2:13][N:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[N:2][OH:3])[C:15]1=[O:16])[CH3:10]
Reactant: NO
Reactant: CCOC(CN1C(=O)C(=O)c2ccccc21)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(CN1C(=O)C(=NO)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A solution of 5.38 g of hydroxylamine hydrochloride and 5.38 g of sodium acetate in 40 ml of water was added to a suspension of 11.1 g of 1-(2,2-diethoxyethyl)isatin in 100 ml of ethanol. The mixture was stirred at room temperature for 1 hour, followed by concentration. The concentrate was diluted with chloroform and washed with an aqueous solution of sodium chloride. The chloroform layer was dried over anhydrous sodium sulfate and concentrated, and the residue was recrystallized from ethyl acetate to obtain 7.10 g (61%) of 1-(2,2-diethoxyethyl)-3-(hydroxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[C:10]([F:18])[CH:9]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:12]([C:11]4[CH:16]=[CH:17][C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:19])=[CH:9][C:10]=4[F:18])=[O:14])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1F
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCCS3(=O)=O)cc2F)CC1
Yield: 83 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)-2-fluorobenzoate (115 mg) described in Preparation Example 200 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (104 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (157 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Product: COC(=O)c1cc(F)c(Br)cc1F
Temperature: 65 °C

Procedure:
A mixture of 4-bromo-2,5-difluorobenzoic acid (i-7b) (0.48 g, 2 mmol) and methanol (10 mL, saturated with gaseous HCl) was heated at 65° C. for 2 h. The mixture was concentrated. Then MeOH was added and the mixture was concentrated again. The residue was purified by flash chromatography (Pentane/EtOAc=4:1) to give the title compound. LCMS (ESI) calc'd for C8H5BrF2O2 [M+H]+: 251. found: 251.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C(O)CCCC>>[CH3:9][O:8][C:7]1[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccnc1Cl
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: COc1cccnc1N1CCNCC1

Procedure:
2-Chloro-3-methoxypyridine, 7 g., 0.05 mole) was allowed to react with 21.5 g. (0.25 moles) of piperazine in the presence of 34.5 g. (0.25 mole) of pulverized potassium carbonate employing 150 ml. of amyl alcohol as reaction medium. The mixture was heated at reflux in a round bottom flask after drying the reaction mixture by distillation. A reflux period of 20 hrs. following elimination of the water was employed. The reaction mixture was filtered while hot and the solvent was removed from the filtrate by distillation. The residue was triturated with chloroform and 1 g. of solid was removed by filtration. The chloroform was removed from the filtrate by distillation yielding 3.88 g. of the desired product which was purified by distillation, b.p. 120°-124°/0.1 mmHg.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]1([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:15][CH2:14]1>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([CH:13]2[CH2:15][CH2:14]2)=[CH:17][CH:18]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(C2CC2)cc1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(C2CC2)cc1
Temperature: 135 °C
Yield: 56.2 %

Procedure:
Isatoic anhydride (0.393 g, 2.41 mmol) and 4-cyclopropylaniline (0.320 g, 2.41 mmol) were dissolved in DMF (5 mL) and heated at 135° C. for 5 hours. The reaction mixture was concentrated, and purified by silica gel chromatography, eluting with 30% ethyl acetate/heptane to 100% ethyl acetate, to afford 2-amino-N-(4-cyclopropylphenyl)benzamide as a white solid (0.342 g, 56%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C1(S([N:20]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[C:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=3)=[CH:21]2)(=O)=O)C=CC=CC=1>>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:31]2[N:30]=[C:29]([C:22]3[C:23]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][CH:21]=3)[CH:34]=[CH:33][N:32]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: CN(C)c1ccc(N)cc1
Product: CN(C)c1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 58.4 %

Procedure:
Using the procedure of example 1, N,N-dimethyl-p-phenylenediamine (221 mg) was reacted with compound 1f (100 mg) to provide compound 38 (52 mg, 29%). 1H NMR (400 MHz, CD3OD) δ 8.85 (d, J=8.0 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=4.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.43 (m, 1H), 7.18 (dd, J=8;0 Hz, 5.6 Hz, 1H), 7.12 (d, J=5.6 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 2.90 (s, 6H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:30])[NH:6][C:7]1[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:16]=2)[N:10]=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.C(C1C=C(NC([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=O)N(C2C=CC(CO)=CC=2)N=1)(C)(C)C>>[C:26]([C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=[O:30])[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:16]=2)[N:10]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from Intermediate 3c and Intermediate 108b using analogous procedures to those described in Intermediate 106a. LCMS (Method 4): Rt 3.27 min, m/z 723.5 [MH+].
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][OH:34]>>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([O:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Reactant: CN(C)CCO
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCCN(C)C)cc1

Procedure:
As in the method of Example 21, 4-(hexadecylamino) hydrocinnamoyl chloride hydrochloride is treated with 2-dimethylaminoethanol to provide 2-dimethylaminoethyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[NH2:18][C:19]1[C:20]([C:26]([NH:28][CH3:29])=[O:27])=[N:21][C:22]([Br:25])=[CH:23][N:24]=1>>[Br:25][C:22]1[N:21]=[C:20]2[C:19](=[N:24][CH:23]=1)[N:18]=[CH:29][N:28]([CH3:1])[C:26]2=[O:27]
Reactant: CCOC(OCC)OCC
Reactant: CNC(=O)c1nc(Br)cnc1N
Solvent: CC(=O)OC(C)=O
Product: Cn1cnc2ncc(Br)nc2c1=O
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of triethyl orthoformate (32.23 g, 36.17 mL, 217.5 mmol) and acetic anhydride (38.49 g, 35.57 mL, 377.0 mmol) was treated with 3-amino-6-bromo-N-methyl-pyrazine-2-carboxamide (6.7 g, 29.00 mmol) and the resulting solution was heated at reflux for 2 hours. After cooling to RT, the resultant precipitate was collected, washed with EtOAc and dried to give the product as a beige solid (5.52 g, 79% Yield). 1H NMR (400.0 MHz, DMSO) d 3.54 (s, 3H), 8.72 (s, 1H); 9.17 (s, 1H) ppm; MS (ES+) 242.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:33]#[C:32][C:26]3[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=3[Cl:24])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Reactant: C#Cc1cc(Cl)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cc(Cl)ccc1Cl
Yield: 18.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1,4-dichloro-2-ethynylbenzene (Intermediate-23, 0.029 g, 0.16 mmol), TBAF (0.101 g, 0.33 mmol), bis(triphenylphosphine)palladium(II) chloride (0.005 g, 0.04 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.49-7.56 (m, 3H), 7.59-7.73 (m, 6H), 12.90 (br s, 1H); MS (m/z): 487.95 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][C:6](=[N:22][OH:23])[C:5]1=[O:24].[CH2:25]([N:28]=[C:29]=[O:30])[CH2:26][CH3:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][C:6](=[N:22][O:23][C:29]([NH:28][CH2:25][CH2:26][CH3:27])=[O:30])[C:5]1=[O:24]
Reactant: CCCN=C=O
Reactant: COCN1C(=O)C(=NO)CN(c2ccccc2F)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)ON=C1CN(c2ccccc2F)c2ccccc2N(COC)C1=O
Yield: 85.2 %

Procedure:
1-Methoxymethyl-2-oxo-3-hydroxyimino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.35 g) was dissolved in tetrahydrofuran (25 ml), propyl isocyanate (1.52 g) and triethylamine (1.81 g) were added thereto, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (silica gel NH-DM1020, produced by Fujisilicia Co. Ltd., chloroform), to thereby obtain 2.52 g of the titled compound as brown amorphous (Yield: 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.C([Sn](CCCC)(CCCC)[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ncnc2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: Cc1ccccc1
Product: Brc1ccc2ncnc(-c3cccs3)c2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
0.6 g 6-bromo-4-chloroquinazoline was dissolved in 18 mL toluene, and 0.82 mL tri-n-butyl(2-thienyl)stannane and 0.14 g tetrakis (triphenylphosphine)palladium (0) were added thereto and stirred at 80° C. for 24 hours under nitrogen atmosphere. After the solvent was evaporated, the residue was purified by silica gel chromatography (hexane/ethyl acetate), to give 0.29 g of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[C:31](=[O:32])[C:30](=[O:33])[C:29]=3[O:34]C(C)C)=[CH:18][CH:17]=2)[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[C:29](=[O:34])[C:30](=[O:33])[C:31]=3[OH:32])=[CH:20][CH:21]=2)[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2c(O)c(=O)c2=O)cc1

Procedure:
Methyl 2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate (0.26 g; preparable as described in Example 27(c)) was heated in a mixture of glacial acetic acid (5 ml) and water (5 ml) at 95°-100° C. for 5 hours. The solvents were evaporated in vacuo and the residue obtained was purified by flash chromatography on silica gel (eluting with 10% rising to 30% industrial methylated spirit in ethyl acetate) to give methyl 2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxo-cyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate, an active compound of the present invention, as a yellow oil (0.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH:2]=[CH:3][C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])[CH:6]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=C(c1ccc(Br)cc1C(F)(F)F)N1CCC[C@H]1CN1CCCC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2-trifluoromethyl-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-methanesulfonylbenzene boronic acid (CAS 149104-88-1). MS (FIA) 481 (MH+)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:10]1([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[CH2:13][O:12][CH2:11]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(COCCCCCCBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCCCCOCC2(C)COC2)cc1
Yield: 80.6 %

Procedure:
A reaction mixture comprising 84 g of 3-[(6-bromohexyloxy)methyl]-3-methyloxetane, 50 g of ethyl 4-hydroxybenzoate, 50 g of potassium carbonate and 600 ml of dimethylformamide was stirred at 90° C. for 4 hours. Water was added to the reaction mixture and the reaction was stopped. This was extracted with ethyl acetate, and the organic layer was washed with aqueous 2 N-sodium hydroxide solution and water in that order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel chromatography (elution solvent:toluene/ethyl acetate=8/2), and 85 g of ethyl 4-[6-(3-methyloxetan-3-ylmethoxy)hexyloxy]benzoate was obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3]>CO.[Pd]>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)NCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)NCC(=O)OC

Procedure:
2.0 g of Z-Ala-Ile-Gly-OMe are dissolved in 40 ml of methanol with gentle warming and then hydrogenated in the presence of 300 mg of Pd on charcoal (10%). After completion of the hydrogenation the catalyst is filtered off and the filtrate completely evaporated to dryness. The residue, which is homogeneous in a thin layer chromatogram, is immediately processed further.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH:27]([C:30]1[CH:34]=[C:33]([CH2:35][S:36](Cl)(=[O:38])=[O:37])[O:32][N:31]=1)([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:34]=[C:33]([CH2:35][S:36]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:37])=[O:38])[O:32][N:31]=1)([CH3:29])[CH3:28]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CC(C)c1cc(CS(=O)(=O)Cl)on1
Solvent: CC(=O)O
Product: CC(C)c1cc(CS(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)on1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and (3-isopropyl-isoxazol-5-yl)-methanesulfonyl chloride. Light yellow solid. MS (ESI): 502.16 (MH+)
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21](Cl)[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21]([NH:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CCOP(=O)(COCCCON)OCC
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(COCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of diethyl 3-aminooxypropoxymethylphosphonate (4 g,16.6 mmol), 4,6-dichloro-2,5-diformamidopyrimidine (3.9 g, 16.6 mmol) and diisopropylethylamine (8.67 ml, 49.8 mmol) in diglyme (80 ml) was heated at 100° C. for 2 h. After removal of the solvent under reduced pressure, the residue was chromatographed in chloroform/methanol (100:1, 50:1, 10:1) affording 4-chloro-6-[3-(diethoxyphosphorylmethoxy)propoxyamino]-2,5-diformamidopyrimidine as a yellow oil (4.61 g, 63%); νmax (film) 3200, 2990, 1690, 1590, 1220, 1040 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.85(2H, m, CH2CH2CH2), 3.65(2H, t, J6.3 Hz, CH2OCH2P), 3.40(2H, d, J8.2 Hz, CH2P), 3.92(2H, t, J6 Hz, CH2ON), 4.04(4H, m, (CH3CH2O)2), 8.15(1H, s, CHO), 9.25(1H, br.s, CHO), 9.43(1H, br.s, D2O exchangeable, NH), 10.76(1H, br s, D2O exchangeable, NH), 10.86(1H, br.s,D2O exchangeable, NH); Found: M+ 439.1015; C14H23ClN5O7P requires: M+ 439.1024.
Reaction SMILES: Cl[CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]#[N:4].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>O>[C:3]([CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)#[N:4]
Reactant: N#CC(Cl)Sc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: O
Product: N#CC(Sc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
Into a 125 ml three-necked round bottom flask are placed 33 g (0.15 mole) of α-chloro-α-p-chlorophenylthioacetonitrile and 33 g (0.48 mole) of imidazole. The mixture is heated to 60° when an exothermic reaction sets in (110°). It is then cooled to room temperature, poured into water and extracted with ether. The combined ether extracts are evaporated to give 20 g of a brown solid which when triturated with ether gives 7 g of pure product, mp 120°-2°.
Reaction SMILES: [NH2:1][C:2](=[S:19])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:20](OC(OCC)CBr)[CH3:21]>CC(C)=O.Cl.O1CCOCC1>[C:5]1([CH2:4][C@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:2]2[S:19][CH:20]=[CH:21][N:1]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=S
Reactant: CCOC(CBr)OCC
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
To a mixture of #13 (5.65 g, 20.2 mmol, 1 eq.) in acetone (101 mL, 0.2 M) was added bromoacetaldehyde diethyl acetal (8.76 mL, 58.2 mmol, 2.89 eq.) and 2 drops of 4 M hydrochloric acid in dioxane. The mixture was degassed with nitrogen three times before being heated to reflux. After 2 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude orange oil was diluted with ethyl acetate before being concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 35% ethyl acetate in heptane) and then by reverse phase chromatography (Method A) to give #14 (625 mg, 10%); HPLC (Protocol E): m/z 304.5 [M+H+], 248.9 [(M−2-methylprop-1-ene)+H+], retention time=7.416 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, major rotamer: δ 7.75 (d, J=3.3 Hz, 1H), 7.75 (br d, J=8.6 Hz, 1H), 7.61 (br d, J=3.1 Hz, 1H), 7.25-7.30 (m, 5H), 4.99 (ddd, J=10.5, 8.9, 4.5 Hz, 1H), 3.29-3.36 (m, 1H, assumed; partially obscured by water signal), 2.98 (dd, J=13.8, 10.6 Hz, 1H), 1.31 (s, 9H).