Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:29])[CH:17]3[NH:21][C:22](OC(C)(C)C)=[O:23])[C:14]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46]S(O)(=O)=O.[S:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[CH2:56]C(Cl)=O.C(N(CC)CC)C>C(#N)C.O1CCCC1>[CH:33]([O:32][CH:30]([CH3:14])[CH3:46])([CH3:34])[CH3:40].[NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:29])[CH:17]3[NH:21][C:22](=[O:23])[CH2:56][C:52]3[S:51][CH:55]=[CH:54][CH:53]=3)[C:14]=2[C:30]([O:32][CH:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:31])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12

Procedure:
3-(2-Anilino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (2.3 g) is treated with methanesulphonic acid (2.3 cc) in acetonitrile (23 cc) in accordance with the working method described in Example 2. Crude 7-amino-3-(2-anilino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.85 g) is obtained and is acylated with (thien-2-yl)-acetyl chloride (0.445 cc) in tetrahydrofuran (25 cc) in the presence of triethylamine (0.505 cc), using the working method described in Example 1. The crude product obtained is chromatographed on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 1.2 bar (120 kPa) with a 70:30 (by volume) mixture (3 liters) of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 20 to 50 are combined and concentrated to dryness. After trituration with isopropyl ether, 3-(2-anilino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2 -yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.9 g) is obtained in the form of a yellow solid.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:66]([O:73][C:74](=[O:80])[CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:79][CH2:78][CH2:77][CH2:76][CH2:75][C:74]([O:73][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:80])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reactant: NCCCCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Boc-Gly-Gly-Phe-Gly-OH (SEQ ID NO. 1) (575 mg), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the solution was stirred for 30 minutes. The resulting solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 560 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1). The Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1) (560 mg) was dissolved in methanol (60 ml) containing 50% of water, and the solution was added with 5% Pd—C (water content; 50%, 1.5 g) and stirred overnight under hydrogen at ordinary pressure. After the catalyst was removed from the reaction mixture by filtration, the mixture was concentrated to dryness to obtain 300 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOH (SEQ ID NO. 1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:26][CH3:27])[CH:4]=1.[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38]([OH:48])=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38]([O:48][CH2:2][C:3]3[CH:25]=[CH:24][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:26][CH3:27])[CH:4]=3)=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc([N+](=O)[O-])c4)oc3C)c(OC)c2)cs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (1.17 g), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol (0.892 g), potassium carbonate (0.415 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v) to give {4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (0.742 g, yield 38%) as colorless crystals. Recrystallization from ethyl acetate-diethyl ether gave pale-yellow prism crystals. melting point: 127-129° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:13][C@@H:14]1[CH2:19][O:18][CH2:17][CH2:16][NH:15]1.C(N(C(C)C)CC)(C)C>C(O)(C)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@H:14]2[CH3:13])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Temperature: 75 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
2,6-Dichloro-9H-purine (2.36 g, 12.5 mmol), (R)-3-methylmorpholin hydrochloride (1.89 g, 13.8 mmol), and diisopropylethylamine (5.46 mL, 31.3 mmol) were dissolved in 15 mL of isopropanol, and the reaction mixture was stirred for 18 hours at 75° C. The reaction mixture was then diluted with 200 mL of CH2Cl2. The organic solvents were washed with aqueous Na2CO3, followed by water and brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (150 g SiO2, CH2Cl2/EtOH/aq NH3 in a ratio of 96/4/0.1) to give the product as a solid (2.87 g, 91%).
Reaction SMILES: CN.C1N=[CH:6][N:5]([C:8]([N:10]2C=N[CH:12]=[CH:11]2)=[O:9])C=1.CCN(C(C)C)C(C)C.NCC[C@@:27]1([C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)[O:32][C:31](=[O:33])[N:30]([C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=3[F:49])=[CH:38][CH:37]=2)[CH3:35])[CH2:29][CH2:28]1>C(Cl)Cl>[F:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[C:39]1[CH:40]=[CH:41][C:36]([C@@H:34]([N:30]2[CH2:29][CH2:28][C@:27]([CH2:12][CH2:11][NH:10][C:8]([NH:5][CH3:6])=[O:9])([C:50]3[CH:51]=[CH:52][C:53]([F:56])=[CH:54][CH:55]=3)[O:32][C:31]2=[O:33])[CH3:35])=[CH:37][CH:38]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
To a solution of methylamine (11 mg, 0.11 mmol) and CDI (20 mg, 0.13 mmol) in anhydrous CH2Cl2 (3 mL) was added DIEA (130 mg, 1.00 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at ambient temperature for 1 h. (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (40 mg, 0.088 mmol) was added to the above mixture, and the mixture was stirred at rt overnight. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to afford 1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-3-methylurea (5 mg, 12%). 1H NMR (CDCl3): 1.56 (m, 3H), 2.10-2.30 (m, 4H), 2.35 (m, 1H), 2.75 (s, 3H), 3.01 (m, 1H), 3.09 (m, 1H), 3.30 (m, 1H), 5.69 (m, 1H), 6.86-6.96 (m, 2H), 7.08 (m, 4H), 7.25 (m, 2H), 7.30 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:21]1([CH3:36])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1C1C=CC=CC=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].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.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:36])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: Cc1ccccc1-c1ccccc1B(O)O
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c(N)s1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(=O)(=O)c2cccc(-c3ccccc3C)c2)c(N)s1

Procedure:
5-Amino-4-(2′-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester was prepared following the procedure as in Example 1: step c using 5-amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (598.9 mg, 1.6 mmol) (Example 20: steps a-c), o-tolyl-phenyl boronic acid (435.6 mg, 3.2 mmol), Pd(PPh3)4 (366.6 mg, 0.32 mmol), aqueous Na2CO3 (2M, 6.4 mL, 12.8 mmol), ethanol (6.4 mL) and toluene (12.8 mL). Purification by flash column chromatography (Biotage Flash™ System—40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the adduct (137 mg, 23%) as a light brown solid. ESI-MS (m/z): Calcd. for C19H17NO4S2: 387.02; found: 388.3. 5-Amino-4-(2′-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (61 mg, 16 mmol) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (6 mg, 10%) as a light brown solid. 1H-NMR (CD3OD): δ: 7.96–7.99 (m, 1H), 7.95 (s, 1H), 7.93–7.94 (m, 1H), 7.63–7.69 (m, 3H), 7.18–7.32 (m, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S2: 372.0 (M+H); found: 372.2.
Reaction SMILES: [CH2:1]([N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=O)[CH2:2][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][CH2:17][CH3:18].[P:40]([OH:43])([OH:42])[OH:41].P(Cl)(Cl)Cl>O>[CH2:1]([N:19]([CH:20]([P:40]([OH:43])(=[O:41])[OH:42])[P:40]([OH:43])(=[O:42])[OH:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:2][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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)CCCCCCCCCCCCCCCCCC
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(P(=O)(O)O)P(=O)(O)O
Yield: 65 %

Procedure:
137 parts of about 90% dioctadecylformamide and 20.5 parts of phosphorous acid were slowly reacted with 34.3 parts of phosphorus trichloride at 70°C and the mixture was maintained for 3 hours at this temperature. At this time, it was hydrolyzed with 500 parts of water. The product was filtered by suction, and the residue was dissolved in alcohol, precipitated again with acetone, isolated and dried in vacuo at 50°C over P2O5. N,N-dioctadecylaminomethanediphosphonic acid was obtained in a yield of 65%.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Br:23])[CH:16]=1)C(OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:23][C:17]1[CH:16]=[C:15]([CH2:7][C:6]([OH:24])=[O:5])[CH:20]=[CH:19][C:18]=1[C:21]#[N:22]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C#N)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CC(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
To the di-tert-butyl(3-bromo-4-cyanophenyl)malonate (2.2 g, 5.4 mmol) in dichloromethane (30 mL) was added triflouroacetic acid (10 mL) and the reaction mixture stirred for 12 h at room temperature. The solution was concentrated under reduced pressure and chased with toluene (2×) to give the crude product as a yellowish oil (1 g, 77%, and 85% purity as indicated by NMR). The residue was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 12.80 (br s, 1H), 7.87 (d, J=8 Hz, 1H), 7.80 (s, 1H), 7.48 (d, J=8 Hz, 1H), 3.73 (s, 2H). LC-MS (IE, m/z): 240 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([O:23][C:17](=[O:22])[CH:18]=[C:19]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([Br:15])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:21])[CH3:25]
Reactant: Nc1ccc(Br)c(OCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1ccc(Br)c(OCc2ccccc2)c1
Yield: 106.2 %

Procedure:
To a mixture of 3-benzyloxy-4-bromo-phenylamine (55.7 g, 0.168 mol) and ethyl acetoacetate (23.4 mL, 0.185 mol) in cyclohexane was added toluene-4-sulfonic acid monohydrate (0.320 g, 1.68 mmol) The reaction mixture was refluxed during 6 h and the water was azeotropically removed. The reaction mixture was then partitioned between ethyl acetate and an aqueous solution of sodium hydrogenocarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 69.6 g of the title compound were obtained. Black oil, ISP-MS: m/e=392.2 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:33]([N:36]([CH:39](C)C)CC)([CH3:35])[CH3:34].ClC(Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl.C(N)(C)C>ClCCl>[F:29][C:28]([F:31])([F:30])[C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:39]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:45])=[CH:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:22][CH:21]=1)([OH:32])[C:24]([F:25])([F:26])[F:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
(4-Aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-piperazin-1-yl)methanone (0.217 mmol, 0.1 g) and diisopropylethylamine (0.737 mmol, 0.122 mL, 0.095 g) were stirred in dichloromethane at room temperature. Triphosgene (0.080 mmol, 0.024 g) was added and the reaction mixture stirred for 30 minutes. Isopropylamine (0.433 mmol, 0.037 mL, 0.026 g) was added and the reaction stirred for a further 30 minutes. The reaction mixture was concentrated under vacuum and purified by reverse phase acidic preparative HPLC to afford the title compound (10 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:12][O:11]2)=[CH:4][N:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[N:23]1[CH2:30][C@H:29]2[NH:31][CH2:32][C@@H:24]1[CH2:25][CH:26]=[CH:27][CH2:28]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:12][N:31]2[CH2:32][C@H:24]3[N:23]([C:14]4[CH:15]=[CH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:13]=4)[CH2:30][C@@H:29]2[CH2:28][CH:27]=[CH:26][CH2:25]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(OC[C@@H]2CO2)cn1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: Cc1ccc(OC[C@@H](O)CN2C[C@@H]3C/C=C\C[C@H]2CN3c2ccc3ccccc3c2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(OC[C@@H](O)CN2C[C@@H]3CC=CC[C@H]2CN3c2ccc3ccccc3c2)cn1
Temperature: 95 °C

Procedure:
(S)-2-Methyl-5-oxiranylmethoxy-pyridine (13 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was removed and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=O)[CH:27]=[CH2:28])[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][NH:31][NH2:32].O1CCCC1>C(OCC)(=O)C>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26]3[CH2:27][CH2:28][N:31]([CH3:30])[N:32]=3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: CNN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(CC2CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of N-methyl-N-{2-[5-(2-oxobut-3-en-1-yl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (250 mg), methylhydrazine (0.050 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the insoluble substance was filtered off, and the filtrate was concentrated. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (156 mg, yield: 59%) as colorless needle crystals. MS:474(MH+). melting point 149-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(c2ccc(F)c(Cl)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Example 22. (+3-(3-chloro-4-fluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.043 mmol), triethylamine (12.1 μL, 0.086 mmol), tetrahydrofuran (2 ml) and iodoethane (5.2 μL, 0.065 mmol). The crude product analyzed by GCMS. Analysis showed 83% conversion. MS m/z (relative intensity, 70 eV) 257 (M+, 4), 242 (34), 227 (20), 157 (32), 71 (bp).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.[N:23]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=N1.C(N(CC)CC)C.O.C(Cl)[Cl:52]>>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10](=[O:12])[NH:25][CH2:26][C:31]1[CH:30]=[C:29]([Cl:52])[CH:28]=[CH:27][N:23]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: ClCCl
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1cc(Cl)ccn1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of N-boc-L-proline (0.50 g, 2.3 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.02 g, 2.3 mmol) in DCM was added triethylamine (1.40 g, 13.8 mmol) and the reaction mixture was stirred for 30 minutes. C-(4-Chloro-pyridin-2-yl)-methylamine dihydrogenchloride (0.50 g, 2.30 mmol) was added and the reaction mixture was stirred for 12 hours. Water was added and the reaction mixture was extracted with DCM. The organic layers were combined, dried with Na2SO4, filtered, concentrated and purified by FCC (0-60% EtOAc in hexane) to provide the desired product (0.93 g, 93%). 1H NMR (400 MHz, DMSO) δ 8.62-8.51 (m, 1H), 8.47 (dd, J=9.8, 5.3, 1H), 7.56-7.31 (m, 2H), 4.45-4.27 (m, 2H), 4.20-4.09 (m, 1H), 3.51-3.24 (m, 2H), 2.26-2.05 (m, 1H), 1.95-1.69 (m, 3H), 1.48-1.24 (m, 9H).
Reaction SMILES: [H-].[Na+].[CH:3]([Si:6]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[O:7][CH:8]1CN[C:11](=O)[NH:10][CH2:9]1)([CH3:5])[CH3:4].CI.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>>[CH3:23][N:24]1[CH2:25][CH:8]([O:7][Si:6]([CH:15]([CH3:17])[CH3:16])([CH:3]([CH3:5])[CH3:4])[CH:18]([CH3:19])[CH3:20])[CH2:9][N:10]([CH3:11])[C:26]1=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)[Si](OC1CNC(=O)NC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)[Si](OC1CN(C)C(=O)N(C)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (141 mmol) was added portionwise to a solution of 5-triisopropylsilanyloxy-tetrahydro-pyrimidin-2-one (Step P9) (28.2 mmol) in DMF (200 mL) at 0° C. After 15 min, the reaction was warmed to rt. After 2 h, the mixture was cooled to 0° C., treated with methyl iodide (197 mmol) and then allowed to warm to rt overnight. The reaction mixture was quenched by addition of water and extracted with toluene. The aqueous layer was washed with EtOAc. The combined organic layers were washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered, and concentrated. The residue was used without further purification. ESI-MS: tR=1.33 min, [M+H]+ 301.3 (LC-MS 1).