Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([CH3:18])=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[NH2:17])C.[OH-].[Na+].Cl>O1CCCC1>[NH2:17][C:8]1[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[CH:6]=[C:5]([CH3:18])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(N)c(C=C(C)C(=O)O)cc1OC

Procedure:
Into 10 ml of tetrahydrofuran (THF), 1.0 g of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid ethyl ester was dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted at 40° C. for 4 hours. After the completion of the reaction, the mixture was cooled with 10 ml of 1-N hydrochloric acid being added thereto, and the precipitated crystal was filtered out, whereby 0.85 g of the aimed compound was obtained (95%).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([S:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[O:7])=[CH:4][CH:3]=1.[C:22](Cl)([Cl:24])=[S:23].[OH-].[Na+].[Cl-].[Ca+2].[Cl-]>C(Cl)(Cl)Cl.O>[Cl:24][C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([S:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[O:7])=[CH:4][CH:3]=1)=[S:23]
Reactant: S=C(Cl)Cl
Reactant: O=C(Sc1c(F)c(F)c(F)c(F)c1F)c1ccc(O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Sc1c(F)c(F)c(F)c(F)c1F)c1ccc(OC(=S)Cl)cc1
Reaction time: 0.17 h

Procedure:
S-(Pentafluorophenyl) 4-(hydroxy)thiobenzoate (6.82 g) in dry chloroform (120 ml) was treated with thiophosgene (2.4 ml). This solution was treated with sodium hydroxide (0.85 g) in water (3 ml) with vigorous stirring for 10 minutes. Stirring was continued for 2 hours, when the solution was treated with calcium chloride and stirred for a further hour. Filtration and evaporation of the filtrate gave the title compound (7.6 g) as a homogeneous oil.
Reaction SMILES: [Cl:1][C:2]1[C:34]([C:35]([C:38]#[N:39])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:28]=[CH:27][C:17]3[N:18]=[C:19]([NH:21][C:22]([CH:24]4CC4)=[O:23])[S:20][C:16]=3[C:15]=2[C:29]#[N:30])[CH:8]=1)=[O:5].N1C=CC=CC=1.C(Cl)(=O)C>O1CCCC1>[C:22]([NH:21][C:19]1[S:20][C:16]2[C:15]([C:29]#[N:30])=[C:14]([O:13][C:9]3[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([C:38]#[N:39])([CH3:37])[CH3:36])[C:2]=4[Cl:1])[CH:12]=[CH:11][CH:10]=3)[CH:28]=[CH:27][C:17]=2[N:18]=1)(=[O:23])[CH3:24]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1Cl
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (8.0 g, 21.1 mmol) produced in Example 3 (iv) in tetrahydrofuran (100 mL) were added pyridine (20 mL, 250 mmol) and acetyl chloride (1.8 mL, 25.3 mmol), and the mixture was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was diluted with ethyl acetate (500 mL). The obtained solution was washed successively with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (6.43 g, 72%) as a white powder.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:14][CH3:15])=[C:8]([N+:11]([O-])=O)[CH:9]=2)[C:4]([CH3:17])([CH3:16])[C:3]1=[O:18]>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([CH3:16])([CH3:17])[C:3](=[O:18])[NH:2]2)=[CH:6][C:7]=1[NH:14][CH3:15]
Reactant: CNc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)C2(C)C
Agent: [Pd]
Solvent: CO
Product: CNc1cc2c(cc1N)NC(=O)C2(C)C
Yield: 88.3 %

Procedure:
1,3,3-Trimethyl-5-methylamino-6-nitro-1,3-dihydro-indol-2-one (176 mg) is dissolved in MeOH (22 ml) and hydrogenated at 3 bar and 40° C. for 5 h using Pd/C (10%) (18 mg). After filtration and evaporation the crude material is purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) to give the title compound (128 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Cl:15][C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2cccc(Cl)c2n1
Product: CC(C#N)(Cn1nc2cccc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 35) and 4-trifluoromethylthiobenzoyl chloride (0.1 mL), the title compound was isolated as a white solid (130 mg, 70%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=440. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.43 (d, J=13.3 Hz, 1H), 5.55 (d, J=13.4 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.75-7.95 (m, 5H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.98 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc(F)cc4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
(4-Fluoro-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (45 mg, 0.16 mmol), acetic anhydride (16 μL, 0.16 mmol), and triethylamine (66 μL, 0.48 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 62 (7 mg, 13% yield) as a oily residue. LC-MS (M+H=325, obsd.=325).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[NH:7][C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2].Cl[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[O:43][CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:43][CH3:44])[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2ccccc2c1CCl
Reactant: CC(=O)N1c2ccccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (72 mg, 172 μmol) in DMF (430 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (42.7 mg, 206 μmol), cesium carbonate (72.9 mg, 224 μmol), and sodium iodide (33.5 mg, 224 μmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-1-acetyl-5-((2-methoxynaphthalen-1-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (49.8 mg, 49%) as an off-white solid. MS m/z 611 (MNa)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:29][CH2:28][CH2:27][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([NH2:26])([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.C(Cl)Cl.CCN(C(C)C)C(C)C.[CH2:42]1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)[O:44][CH2:43]1>O.C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:29][CH2:28][CH2:27][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([NH:26][C:43](=[O:44])[CH3:42])([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)(N)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)NC(C)(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.4 %

Procedure:
A flask was charged with 2-(6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-amine (0.125 g, 0.316 mmol, prepared using General Procedure I.1 from Example #6, Step B with Example #9, Step A, General Procedure D with hydrazine hydrate, General Procedure E.1 with tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate (prepared using General Procedure A.I.1 from tert-butyl 1-hydroxy-2-methylpropan-2-ylcarbamate), General Procedure Q.1 with HCl) and DCM (2.0 mL) to give a brown solution. To the reaction flask were added DIPEA (0.166 mL, 0.948 mmol) and HOAC (0.022 mL, 0.38 mmol). BOP-Cl (0.161 g, 0.632 mmol, Lancaster) was added in one portion to the solution and the reaction mixture was stirred at ambient temperature for about 90 min. The mixture was poured into DCM (about 30 mL) and washed with 1N HCl (about 30 mL). The aqueous layer and the organic solution was then washed with 5 N HCl (about 2×30 mL). The aqueous solution was basified with 6N NaOH (about 20 mL). The cloudy solution was back-extracted with DCM (2×50 mL). The organic solution was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give a yellow residue. The product was dissolved into hot ACN (about 4 mL) followed by the addition of water (about 2 mL). The mixture was concentrated under reduced pressure and then lyophilized to give the title compound (0.060 g, 43%): LC/MS (Table 1, Method g) Rt=1.67 min; MS m/z: 474.2 (M+H)+.
Reaction SMILES: [CH2:1]([P:3](Cl)([CH2:5][O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8])=[O:4])[CH3:2].[CH:19]([OH:23])([CH2:21][CH3:22])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([P:3]([CH2:5][O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8])(=[O:4])[O:23][CH:19]([CH2:21][CH3:22])[CH3:20])[CH3:2]
Reactant: CCC(C)O
Reactant: CCP(=O)(Cl)COS(=O)(=O)c1c(C)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)OP(=O)(CC)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 5.83 g of P-ethyl[[(2-chloro-6-methylphenyl)sulfonyloxy]-methyl]phosphinoyl chloride (Example 51) and 0.2 g of 4-dimethylaminopyridine (DMAP) in 15 ml of methylene chloride at 10° C. was added dropwise over 10 minutes a solution of 1.52 g of sec-butanol and 2.32 g of triethylamine in 8 ml of methylene chloride. After 1 hour, the cooling bath was removed and the reaction was warmed to room temperature and stirred an additional two hours. The reaction mixture was diluted with ethyl acetate, 20 ml, ether, 50 ml, and water, 60 ml, and the organic phase was separated, washed with an additional 50 ml of water, dried with magnesium sulfate, filtered and concentrated. The resulting oil was dissolved in 4 ml of methylene chloride and flash chromatographed on Merck silica gel using blends of ethyl acetate and hexanes. Similar fractions were combined to yield 3.2 g of desired product as a tan oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)C.Br[CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>C1C=CC=CC=1>[Br:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: Brc1ccc(OC2CCNCC2)cc1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: c1ccccc1
Product: Brc1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Reaction time: 22 h

Procedure:
A mixture of 8.1 g of 4-(p-bromophenoxy)piperidine hydrochloride, 12.6 g of potassium carbonate and 60 ml. of isopropanol is stirred and refluxed for one hour. A solution of 6.5 g of 3-(2-bromoethyl)indole in 15 ml. of isopropanol is then added. Stirring and refluxing is continued for 22 hours, and the reaction mixture is filtered hot. A yellow oil separates in the cooled filtrate and the supernatant isopropanol is decanted from the oil. The isopropanol is diluted with ether, causing the unreacted 4-(p-bromophenoxy)piperidine to separate. After filtration, the isopropanol is removed under reduced pressure to give a yellow oil. The oil is permitted to stand for 3 weeks during which time it solidifies to a soft brown solid. Trituration of the solid with benzene affords yellow crystals, which are recrystallized from acetonitrite to give slightly yellow cubes of 3-{2-[4-(p-bromophenoxy)piperidyl]ethyl]-indole, m.p. 132°-134° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14]>O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: CCN(CC)CCN
Solvent: O
Product: CCN(CC)CCNc1cc(Cl)cc(NCCN(CC)CC)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added portionwise, with stirring, to 180 ml of N,N-diethylethylenediamine, heated to 60° C. After the end of the addition, heating is continued for 30 minutes. The reaction mixture is diluted with 180 ml of iced water. The expected product precipitates. It is filtered off, washed with water and then dried under vacuum at 60° C. in the presence of phosphorus pentoxide. After recrystallization from 96° ethanol, it melts at 90° C.
Reaction SMILES: C(N1CC[C@@H:5]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2S(NC2C(C(OC)=O)=C3C(C4CC4CO3)=CC=2)(=O)=O)=O)C1)C.[F:38][C:39]([F:44])([F:43])[C:40](O)=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([N:8]1[CH2:5][CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH2:9]1)=[O:41]
Reactant: O=C(O)C(F)(F)F
Reactant: CCN1CC[C@@H](NC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Solvent: ClCCl
Product: O=C(N1CC(c2cccc(F)c2)C1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 3-(3-fluorophenyl)azetidine-1-carboxylate (Intermediate 92, 2.51 g) in trifluoroacetic acid (15 mL) and DCM (15 mL) was left to stand at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was azeotroped with toluene. The residue was dissolved in DCM (15 mL) and pyridine (5 mL) and trifluoroacetic anhydride (3.15 g) was added. The mixture was left to stand at room temperature for 30 minutes, then washed with 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give 2,2,2-trifluoro-1-[3-(3-fluorophenyl)azetidin-1-yl]ethanone (2.31 g) as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28]Cl)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:22][CH2:21]1
Reactant: CC(CCl)CN1CCOCC1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Agent: Cl
Product: CC(COc1c(-c2ccccc2)c(=O)oc2ccccc12)CN1CCOCC1
Yield: 82.5 %

Procedure:
This compound is prepared according to the method of Example 8 from 14.3 g. (0.06 mol) of 4-hydroxy-3-phenyl-coumarin and 16.7 g. (0.078 mol) of 3-morpholino-2-methyl-1-chloropropane hydrochloride. After recrystallisation from ethanol, 18.8 g. are obtained. Yield 82.5% (theoretical yield 22.8 g.); M.P. 113° C.
Reaction SMILES: [F:1][C:2]1([F:27])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:29]1[O:30][C:31]([CH3:34])=[N:32][N:33]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:27][C:2]1([F:1])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][N:4]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)[CH2:3]1
Reactant: Cc1nnc(Br)o1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5F)cccn4n3)C(F)(F)C2)o1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A solution of N-(3,3-difluoropiperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (see example 275b, 75 mg, 196 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (41.5 mg, 254 μmol) and diisopropylethylamine (50.6 mg, 68.3 μL, 391 μmol) dissolved in dry dioxane (4 mL) was stirred at 110° C. for 3 hours. Further diisopropylethylamine (50.6 mg, 68.3 μL, 391 μmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (41.5 mg, 254 μmol) were added and heated to 110° C. for 12 hours. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was as white foam (36 mg, 40%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].N[C@@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCC(=O)O.N[C@@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CCC(=O)N.N[C@@H](C(O)=O)CCC(=O)N>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: N[C@H](CC(=O)O)C(=O)O
Agent: NC(=O)CC[C@@H](N)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)C[C@@H](N)C(=O)O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
replace with: D-Asp, D-Asn, Asn, Glu, D-Glu, Gln, D-Gln;
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:11]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:23]([N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:13])=[O:14])[C@@H:10]([C:9]([OH:32])=[O:8])[C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: COc1cccc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)O)C(C)(C)C)c1
Yield: 99.5 %

Procedure:
To a solution of N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucine benzyl ester (2.0 g, 4.33 mmol) in MeOH (12 ml) is added 10% palladium on carbon (200 mg) and the reaction is stirred under ambient pressure of hydrogen for 4 hours. The reaction is filtered through celite and concentrated affording the title compound (1.6 g, 99%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[O:13]=[S:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][NH:15]1>>[O:13]=[S:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][N:15]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: O=S1(=O)CCCN1
Reactant: COC(=O)c1ccc(CBr)nc1
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Yield: 73 %

Procedure:
Using methyl 6-bromomethylnicotinate (500 mg) and 1,1-dioxo-1λ6-isothiazolidine (290 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (429 mg) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH:7](O)[CH2:8][CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:4]=[CH:3]1.CS(O)(=O)=O.[OH-].[Na+]>O>[C:11]1([CH:10]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:7]([C:5]3[N:4]=[CH:3][NH:2][CH:6]=3)[CH2:8][CH2:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC(CCC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: c1ccc(C2CCC(c3c[nH]cn3)c3ccccc32)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(1H-imidazol-4-yl)-4,4-diphenylbutan-1-ol hydrochloride (2.0 g) and methanesulfonic acid (40 ml) was heated at 100° C. for 40 minutes. The cooled reaction mixture was poured into water and was made alkaline with sodium hydroxide solution. The product was extracted into ethyl acetate, which was washed with water, dried with sodium sulfate and evaporated under reduced pressure to give a crude product of racemic cis and trans diastereomers. The product was purified by flash chromatography (elution with a dichloromethane—methanol gradient). The base product was dissolved in ethyl acetate and converted to its hydrochloride salt with hydrogen chloride gas.