Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.C[O:46]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.O1C=CC=C1B(O)O>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[CH:9]=[C:8]([O:39][CH3:40])[CH:7]=[CH:6][C:5]=2[C:4]2[O:46][CH:43]=[CH:42][CH:41]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: OB(O)c1ccco1
Product: COc1ccc(-c2ccco2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 5 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 2-furanboronic acid (30 mg, 0.2625 mmol) to produce the title compound (5 mg, 5% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15]C)=[O:14])[O:10][C:11]=2[CH3:12])=[C:5]([CH3:17])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[O:10][C:11]=2[CH3:12])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)O)oc1C
Yield: 92.3 %

Procedure:
A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (60 mg, 0.26 mmol) in 6N sodium hydroxide (0.8 ml, 5.1 mmol) and tetrahydrofuran (2.5 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (53 mg, 0.24 mmol, 94% yield) as a white foam: LCMS (ES) m/e 221 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([N+:49]([O-:51])=[O:50])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[C:41]([N+:49]([O-:51])=[O:50])[CH:40]=2)/[C:36]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
A solution of triphenylphosphine (720 mg, 2.75 mmol) in methylene chloride (25 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (490 mg, 2.75 mmol). The reaction mixture was stirred at 0° C. For 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-nitro-phenyl)-acrylic acid (485 mg, 1.37 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (412 mg, 4.12 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (70 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 to 3/2 hexanes/ethyl acetate) afforded the (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-thiazol-2-yl-acrylamide (122 mg, 20%) as an amorphous solid: EI-HRMS m/e calcd for C19H21N3O5S2 (M+) 435.0923, found 435.0923.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[Cl:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[Cl:31][C:30]1[C:25]([NH:24][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH:9]=[CH:10][C:2]=2[F:1])=[C:26]([F:33])[C:27]([OH:32])=[CH:28][CH:29]=1
Reactant: Nc1c(Cl)ccc(O)c1F
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1c(Cl)ccc(O)c1F)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (478 mg, 2.04 mmol, 1.0 eq) and (COCl)2 (777 mg, 6.13 mmol, 3.0 eq) in DCM (20 mL) was added DMF (0.3 mL). The reaction mixture was stirred at 0° C. for 1 h, then the solvent removed in vacuo. The residue obtained was dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-4-chloro-2-fluoro-phenol (intermediate X(d)) (330 mg, 2.04 mmol, 1.0 eq) and NaHCO3 (515 mg, 6.13 mmol, 3.0 eq) in THF (20 mL). After the addition, the reaction mixture was stirred at room temperature for 30 min. The THF was evaporated in vacuo and the aqueous solution adjusted to pH 3 by addition of 1M HCl. The mixture was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1) to give the title compound as a yellow solid (200 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:8][C:5]2=[N:6][CH:7]=1.[F:14][C:15]([F:25])=[CH:16][CH:17]1[CH2:21][N:20]([CH2:22]O)[C:19](=[O:24])[CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:8]([CH2:22][N:20]3[CH2:21][CH:17]([CH:16]=[C:15]([F:25])[F:14])[CH2:18][C:19]3=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2nc(C3CC3)[nH]c2c1
Reactant: O=C1CC(C=C(F)F)CN1CO
Product: O=C1CC(C=C(F)F)CN1Cn1c(C2CC2)nc2cc(Br)cnc21
Yield: 25 %

Procedure:
1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 272 is synthesized according to the procedure described in example 61 using 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine x168 and 4-(2,2-difluorovinyl)-1-(hydroxymethyl)pyrrolidin-2-one x142.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)=[CH:24][CH:23]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:31]2[CH:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([CH2:21][O:20][CH3:19])=[CH:27][CH:26]=3)[N:29]=[CH:30]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COCc1ccc(-c2c[nH]cn2)cc1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(-c2cn(-c3cc(C(=O)OC)c([N+](=O)[O-])cc3C(F)(F)F)cn2)cc1
Yield: 95.2 %

Procedure:
A mixture of 1.00 g (3.74 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.775 g (4.12 mmol) of 4-(4-methoxymethyl-phenyl)-1H-imidazole in 10 ml of tetrahydrofuran are refluxed for 2 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase separated and washed with brine, dried over Na2SO4 and concentrated to dryness. The residue is purified by flash chromatography on silica (40-63 μm particle size) with ethyl acetate/hexane 2:3, yielding 1.55 g of 5-[4-(4-methoxymethyl-phenyl)-imidazol-1-yl]-2-nitro-4-trifluoromethyl-benzoic acid methyl ester acid as a yellow powder, m.p.=135-137° C. 1H-NMR (DMSO-d6, 400 MHz): 3.30 s, 3H; 3.95 s, 3H; 4.42 s, 3H; 7.35 d, J 10.4 Hz, 2H; 7.82 d, J=10.4 Hz, 2H; 8.02 s, 1H; 8.05 s, 1H; 8.30 s, 1H; 8.72 s, 1H.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](O)=[O:10]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)cc1
Product: O=CNc1ccc(Cl)cc1
Yield: 88 %

Procedure:
4-Chloroaniline (10 g, 78.4 mmol) and formic acid were heated to reflux for 30 minutes. The reaction mixture was concentrated in vacuo. Water was added and basified with sodium carbonate and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtrated and evaporated to give N-(4-chloro-phenyl)-formamide (10.7 g, 88%).
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:28]>C1COCC1>[ClH:28].[ClH:28].[NH2:8][CH:9]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2CN3CCC2CC3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-p-tolylacetate (C41) (250 mg, 0.67 mmol) in THF (50 ml), was added 37% hydrogen chloride (1.0 ml, 12.2 mmol), and the reaction was stirred at RT for 15 hours. The solvent was evaporated to obtain (R)-quinuclidin-3-yl 2-amino-2-p-tolylacetate dihydrochloride (232 mg; quantitative yield).
Reaction SMILES: Cl[C@H:2]([C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5]CC)=[O:4].[O-]CC.[Na+].C(O)C.[OH-].[K+]>C(O)C>[CH2:9]([C@H:8]1[O:12][C@@H:2]1[C:3]([OH:5])=[O:4])[CH2:10][CH3:11]
Reactant: CCC[C@@H](O)[C@@H](Cl)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCC[C@H]1O[C@@H]1C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Ethyl (2R,3R)-2-chloro-3-hydroxyhexanoate (5.0 g, 22 mmol) and ethanol (15 ml) were mixed, and the mixture was cooled to 5° C. To the mixture, 20% sodium ethoxide/ethanol solution (8.3 g, 24 mmol) was gradually added. The mixture was stirred at room temperature for 1 hour. The precipitated inorganic salt was separated by filtration. Potassium hydroxide (1.24 g, 24 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 14 hours. The solvent was evaporated away under reduced pressure, and water (15 ml) was added. The pH was adjusted to 1.8 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (20 ml). The solvent was evaporated away under reduced pressure to obtain the title compound (2.33 g, yield: 65%).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:18][C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:13]=2[C:12]2[O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[CH:7]=1
Reactant: c1ccc2c(c1)ccc1c3ccccc3oc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c3ccccc3oc2c2ccccc12
Temperature: 60 °C
Yield: 82 %

Procedure:
32.7 g of benzo[b]naphtho[2,1-d]furan was dissolved in 300 mL of N,N-dimethylformamide. Then, 50 mL of a N,N-dimethylformamide solution of 28.0 g of N-bromosuccinimide was added, and the resulting reaction solution was stirred with heating at 60° C. for 5 hours. After cooling to room temperature, the reaction solution was poured in 2 L of water. Solids thus obtained were sequentially washed with methanol, water and methanol. The resulting crude product was purified by means of silica gel column chromatography, whereby 36.5 g (yield: 82%) of 5-bromobenzo[b]naphtho[2,1-d]furan was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[CH3:39][CH:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH3:41].[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:45]4[CH2:46][CH2:47][N:42]([CH:40]([CH3:41])[CH3:39])[CH2:43][CH2:44]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)N1CCN(Cc2nnc(-c3cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc4[nH]ncc34)o2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (25 mg, 0.042 mmol) and 1-(1-methylethyl)piperazine (500 mg, 3.90 mmol) were placed a vial and heated in a microwave at 90° C. for 15 mins. The 1-(1-methylethyl)piperazine was blown off under a stream of nitrogen and the residue suspended in isopropanol (2 ml) and 2M sodium hydroxide (1 ml) added. The mixture was stirred at room temperature for 2 h. The solvent was blown off under a stream of nitrogen and the residue purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound as a pale yellow gum (4 mg).
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:16][C@@H:17]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:18](O)=[O:19].N1C=CC=CC=1.Cl.[O:42]=[C:43]1[CH2:48][CH2:47][C:46]([NH2:55])([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[CH3:16][C@@H:17]([C:21]1[CH:22]=[C:23]([C:31]([F:32])([F:34])[F:33])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1)[C:18]([NH:55][C:46]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][CH2:44][C:43](=[O:42])[CH2:48][CH2:47]1)=[O:19]
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Reactant: C[C@H](C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.8 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (672 mg, 2.64 mmol) was added to a solution of (S)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 40, 500 mg, 1.76 mmol) and pyridine (284 μL, 3.52 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 5 minutes. 4-Oxo-1-phenylcyclohexylamine hydrochloride (Description 18, 500 mg, 2.64 mmol) was added and the mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane:EtOAc (65:35). The residue was crystallised twice from propan-2-ol/water (50:50, 20 mL) and the solid was collected and dried in vacuo to give the title compound as a colorless solid (200 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H m), 5.71 (1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz). e.e. [Determined by chiral HPLC (Chiralcel OD-H 250×4.6 mm i.d.; isohexane/EtOH (96:4); 1 mL/min; 210 nm]>99%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl[C:8]1[N:9]([CH3:27])[CH:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1>>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:8]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:9]([CH3:27])[C:10]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(C2N=C(Cl)N(C)C2c2ccc(C)cc2)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 1, Step C, but using ethyl chloroformate, 2-chloro-4,5-di-(4-methylphenyl)-1-methylimidazoline (0.10 g, 0.33 mmol) from Example 2, Step B was converted to the title compound.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH2:18])[CH2:6]1)[CH:2]=[CH2:3].FC(F)(F)C(N[C@@H:24]1[C:32]2C(=CC=C(OC(C)C)C=2)[C@H](O)[CH2:25]1)=O>>[CH2:1]([O:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:32]=[CH:24][CH:25]=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[CH:7]([NH2:18])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: CC(C)Oc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCOC1CC(N)c2cc(Oc3ccccc3)ccc21

Procedure:
Step BB (1). 3-(Allyloxy)-6-phenoxy-2,3-dihydro-1H-inden-1-amine was prepared using a series of procedures analogous to Steps AU (1-5), X (1) and U (2). 1H NMR (300 MHz, CDCl3) δ 1.6-1.8 (m, 1H) 2.7-2.9 (m, 1H) 4.0-4.2 (m, 3H) 4.7-4.8 (t, 1H) 5.1-5.4 (m, 2H) 5.8-6.0 (m, 1H) 6.8-7.1 (m, 5H) 7.2-7.4 (m, 3H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CO.CCOC(C)=O>C(O)=O>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=CO
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Temperature: 0 °C
Yield: 90 %

Procedure:
A 3.911 g (9 mmol) amount of Boc-Trp-Met-NH2 (I) was dissolved in 40 ml of formic acid at room temperature. After complete Boc-removal (TLC monitoring) the solvent was evaporated in vacuo at 30° C. The residue was dissolved in methanol cooled to 0° C., and 3.6 ml (10.8 mmol) of a 3M solution of hydrogen chloride in anhydrous tetrahydrofuran were added. Solvents were removed in vacuo, and 3 g (90% yield) of compound II were obtained from MeOH/AcOEt: m.p. 114° C. (D); [α]D20 =+20.4° (c=1 MeOH): RfC 0.62; E1.2 0.82.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][C:29]=1[N+:37]([O-])=O>>[CH3:27][C:28]1[S:32][C:31]([S:33](=[O:35])(=[O:34])[NH2:36])=[CH:30][C:29]=1[NH:37][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: Cc1sc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1sc(S(N)(=O)=O)cc1NC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid amide (example B.11 ) according to general procedure II. Yellow solid. MS (ISP) 548.1 [(M−H)−]; mp 297° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxyphenylboronic acid (CAS RN 5720-06-9). Off-white solid (45%). MS (ESI): m/z=455.4 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([NH2:14])[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1>>[C:2]([CH2:3][C:4]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[O:5])(=[O:6])[CH3:1]
Reactant: Nc1cccc(N)c1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)Nc1cccc(NC(=O)CC(C)=O)c1

Procedure:
The process of the invention for the preparation of compounds of formula I wherein R' is ##STR11## comprises reacting diketene with m-phenylenediamine to obtain m-(acetylacetamido)-acetylacetanilide which is reacted with methyl orthoformate and then heated to obtain m-(3'-methoxycrotonylamino)-3 -methoxy-crotonanilide.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:5]=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1.C(#N)C.O.FC(F)(F)C(O)=O>CCOC(C)=O.C1COCC1>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:5]=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(OC(F)F)cn3)cc2)C1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)Oc1cnc(Nc2ccc([C@@H]3CNCCO3)cc2)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
(R)-tert-Butyl 2-(4-(5-(difluoromethoxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (58 mg) was combined with acetonitrile (2 ml) and water (6 ml). Trifluoroacetic acid (138 μl) was added. The vial was capped and shaken at 80° C. for 4 hours. The reaction mixture was then poured into EtOAc/THF (1:1) and washed with 1 M aq. NaOH. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (R)-5-(difluoromethoxy)-N-(4-(morpholin-2-yl)phenyl)pyrimidin-2-amine (31 mg, 70%) as a white solid. MS (ISP): 323.1 ([M+H]+).