Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:18])[CH3:19])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:26])=[C:23]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)[CH:22]=1
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 50 %

Procedure:
A mixture of [4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 4-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (52.0 mg, 50.5%). MS (ESI) mass calcd. for C22H25FN8O2, 452.49; m/z found [M+H]+. 1H NMR (CDCl3): 7.83-7.66 (m, 3H), 7.42-7.36 (m, 1H), 7.16-7.08 (m, 1H), 5.00-4.89 (m, 1H), 3.90-3.78 (m, 4H), 3.77-3.19 (m, 6H), 3.17-2.82 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH:38]([CH3:40])[CH3:39])[CH2:36][OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH:35]([CH2:36][OH:37])[CH:38]([CH3:40])[CH3:39])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: CC(C)C(N)CO
Product: CC(C)C(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-3-methyl-1-butanol using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.38 (1H, d, J=9 Hz), 8.55 (1H, s), 8.14 (1H, s), 7.40 (2H, dd, J=6, 9 Hz), 7.13 (2H, t, J=9 Hz), 4.87 (1H, t, J=5 Hz), 4.30-4.50 (2H, m), 4.16 (2H, s), 3.79-3.87 (1H, m), 3.32-3.60 (7H, m), 1.89-2.04 (2H, m), 1.71-1.81 (2H, m), 0.90 (6H, dd, J=7, 9 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].Cl.[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25][NH:24]1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25][N:24]1[CH2:2][C:3]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:4]
Reactant: COc1ccc(CC2NCCOc3cc(OC)c(OC)cc32)cc1OC
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Br)CBr
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3OCCN2CC(=O)NC2Cc3ccccc3C2)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:35])[C@H:11]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:12][C:13](=[O:24])[CH:14]([CH2:19][S:20]C(=O)C)[CH2:15][CH2:16][CH2:17][NH2:18].[OH-].[Na+].[H][H]>CO>[NH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][SH:20])[C:13]([NH:12][C@H:11]([C:10]([OH:35])=[O:9])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:24]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCN)CSC(C)=O
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCCCC(CS)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
To a solution of N-(2-acetylthiomethyl-5-aminopentanoyl)-L-tryptophane methyl ester trifluoroacetate (3 g) in methanol (60 ml) N sodium hydroxide (60 ml) is added. After 4 hours the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. After washing with water, the N-(5-amino-2-mercaptomethylpentanoyl)-L-tryptophane is eluted with pyridine-acetic acid buffer at pH 6.5.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 95 %

Procedure:
To a solution in which 1,2-phenylenediamine (0.5 mmol) was dissolved in pyridine (1 mL) was added p-toluenesulfonyl chloride (1.1 mmol) at room temperature, and the mixture was reacted for 6 hours with stirring. After completion of the reaction, the reaction mixture was diluted with dichloromethane, and back extracted using 1N hydrochloric acid to remove pyridine. After the organic layer was dried with anhydrous sodium sulfate, and concentrated. The obtained solid was washed using diethyl ether on a Buchner funnel, and dried under reduced pressure to obtain an objective substance as a white solid in a yield of more than 95% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][O:27][CH2:26]1)[CH2:10][NH:11][C:12](=[O:23])OC1C=CC([N+]([O-])=O)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:32](C(F)(F)F)=O.[Cl:38][C:39]1[CH:40]=[C:41]([C@@H:45]([C@@H:53]2[CH2:58][CH2:57][CH2:56][NH:55][CH2:54]2)[O:46][CH2:47][CH2:48][NH:49][C:50](=[O:52])[OH:51])[CH:42]=[CH:43][CH:44]=1>>[C:6]([NH:8][C@@H:9]([CH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][O:27][CH2:26]1)[CH2:10][NH:11][C:12]([N:55]1[CH2:56][CH2:57][CH2:58][C@@H:53]([C@H:45]([C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([Cl:38])[CH:40]=2)[O:46][CH2:47][CH2:48][NH:49][C:50](=[O:51])[O:52][CH3:32])[CH2:54]1)=[O:23])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: O=C(O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)C[C@H]1CCCOC1
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)NC[C@H](C[C@H]2CCCOC2)NC(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To (4-nitrophenyl) (S)-2-(N-(tert-butoxycarbonyl)amino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamate solution (2 mL, 0.013 mmol) was added 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate TFA salt (7.0 mg, 0.016 mmol), followed by excess TEA (0.3 mL). The mixture was stirred for 30 min, then the solvent was removed in vacuo. The resulting oil was purified on preparative HPLC to give methyl 2-((R)—((R)-1-((S)-2-(Boc-amino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate 5 mg, yield 63%. MS ESI +ve m/z 611 (M+H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:26]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:34][C:35]([CH3:37])=[O:36]>CN(C=O)C>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:26]=1)[C:6]1[CH:7]=[C:8]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([O:19][CH2:34][C:35](=[O:36])[CH3:37])=[CH:15][CH:14]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cccnc3)cc12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A vial was charged with (S)-2-amino-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.300 g, 0.869 mmol), cesium carbonate (0.425 g, 1.303 mmol). DMF (3.47 mL) was added, the vial was sonicated for 30 s, and the mixture was stirred vigorously for 20 min, at which time some white solid still remained. The vial was cooled in an ice-bath for 10 min, then 1-chloroacetone (0.083 mL, 1.042 mmol) was added dropwise and the reaction was stirred over the weekend, during which the bath warmed to RT. The reaction was cooled back to 0° C. and 1-chloroacetone (0.083 mL, 1.042 mmol) was added. The reaction was stirred for two hours before 0.5 equivalents of cesium carbonate and chloroacetone were added at one hour intervals until the reaction was complete. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-5% MeOH:DCM) to afford (S)-1-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)propan-2-one as a white solid. The remaining fractions were combined and concentrated to afford impure material as an off-white solid.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[SH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:16]I>C(O)C>[CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Sc1nccn1N=Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CSc1nccn1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.16 g of 1-benzylideneamino-2-mercaptoimidazole are suspended in 30 ml of absolute ethanol and treated with a solution of 1.15 g of sodium in 70 ml of absolute ethanol. After the addition of 7.1 g of methyl iodide, the reaction mixture is stirred at room temperature for 3 hours. For the work-up, the resulting yellow solution is concentrated to a quarter and 100 ml of water are added. The resulting crystalline crude product is removed by filtration, washed three times with water and recrystallized from methanol/water. There is obtained 1-benzylideneamino-2-methylmercaptoimidazole of m.p. 95°-97°.
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:41])[NH2:28])=[CH:25][CH:26]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 84 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 84% of theory, C27H28N6O3 (484.56); Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=485.
Reaction SMILES: [CH2:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>O>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][N:40]2[C:17](=[O:19])[CH2:18][CH:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[O:16])=[O:38])[CH:25]=[C:24]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]=1[OH:30])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-dodecylsuccinic anhydride (42.17 g, 147.4 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (43.31 g, 147.4 mmol) and 70 ml of toluene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The bulk of the solvent was distilled off followed by vacuum stripping of the hot (160° C.) melt for about 10 minutes. The resulting yellow liquid was then cooled under vacuum to about 120° C. The vacuum was released and the melt was quickly poured into a container. Upon cooling, the liquid became a clear yellow glass. The product was recrystallized from acetone/water at ice bath temperatures to afford, after drying, a nearly quantitative recovery of the product as a white powder having a melting range of 55°-60° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[OH-].[Na+]>>[ClH:1].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[C:6]3=[CH:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:28][CH2:27]1
Reactant: O=C1Nc2ccc(CCl)cc2C1=Cc1c[nH]c2ncccc12
Reactant: OCCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: O=C1Nc2ccc(CN3CCN(CCO)CC3)cc2C1=Cc1c[nH]c2ncccc12

Procedure:
A mixture of 5-(chloromethyl)-3-[(7-azaindol-3-yl) methylene]-2-oxindole (3.098 g, 10 mmol), 4-hydroxyethyl-piperazine (2.604 g, 20 mmol) in 1N NaOH (20 ml, 20 mmol) was refluxed for 48 h. The cooled reaction mixture was extracted with ether, and the ether extract was shaken with diluted hydrochloric acid. The aqueous acid layer was made alkaline with potassium carbonate and extracted with ether. Addition of hydrogen chloride to the dried ether extract precipitated a crude hydrochloride which was crystallized twice from a mixture of methanol and ether.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CCN)C1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)C1
Temperature: 120 °C
Yield: 28.6 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (74 mg, 0.249 mmol) was dissolved in dry DMF (1 mL) nitrogen atmosphere. tert-Butyl 3-(2-aminoethyl)azetidine-1-carboxylate (50 mg, 0.249 mmol) was added followed by TEA (25 mg, 0.247 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (33 mg, 28.8%). 1H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 1.62 (q, 2H), 1.73 (s, 9H), 2.19-2.27 (m, 1H), 2.83 (q, 2H), 3.23-3.26 (m, 2H), 3.84 (t, 2H), 5.25 (t, 1H), 7.42-7.51 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 26.24, 27.82, 28.61, 34.35, 41.72, 54.06, 61.82, 79.63, 107.55, 125.15, 128.93, 130.09, 131.79, 135.04, 156.38, 159.81; Mass Spectrum: M−H+ 462.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[F:26].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.CCOC(C)=O>ClCCl.CCCCCCC>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)=[CH:21][C:20]=1[F:26]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: Fc1cc(OC2CCCCO2)ccc1Br
Yield: 33 %

Procedure:
Pyridinium p-toluene sulfonic acid (789 mg, 3.1 mmol) was added to a solution of 4-bromo-3-fluorophenol (4.00 g, 20.9 mmol) and 3,4-dihydro-2H-pyran (3.52 g, 41.9 mmol) in dichloromethane (105 mL, 0.2M). After 2 h the reaction was quenched with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted with dichloromethane (2×). The organic layers were combined, dried (Na2SO4), filtered and concentrated to give a colorless oil. The material was loaded onto a 25 g silica guard column and run on a 330 g column with 0-5% EtOAc in heptane. Desired material was concentrated down yielding 1900 mg (33%) of a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56-1.77 (m, 3H) 1.82-1.89 (m, 2H) 1.89-2.07 (m, 1H) 3.62 (m, J=11.37, 4.07, 4.07, 1.37 Hz, 1H) 3.85 (ddd, J=11.32, 10.05, 3.02 Hz, 1H) 5.38 (dd, J=3.12 Hz, 1H) 6.76 (ddd, J=8.88, 2.73, 1.07 Hz, 1H) 6.89 (dd, J=10.34, 2.73 Hz, 1H) 7.35-7.46 (m, 1H).
Reaction SMILES: FC1C(O[C:9]([C:11]2([F:30])[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[CH:19][C:14]3=[N:15][CH2:16][N:17]([CH3:18])[C:13]3=[CH:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH3:35]>CN(C=O)C>[F:30][C:11]1([C:9]([NH2:35])=[O:10])[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:14]2=[N:15][CH2:16][N:17]([CH3:18])[C:13]2=[CH:12]1
Reactant: N
Reactant: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)C=C21
Solvent: CN(C)C=O
Product: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(N)=O)C=C21
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
A reaction vial was charged with the product of Example 1, Step J, 5-fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid pentafluorophenyl ester (0.5229 g, 0.8585 mmol) and DMF (1 mL). Saturated aqueous ammonia (3 mL) was added to the solution, giving a white precipitate immediately. The mixture was stirred for 10 minutes and then was vacuum-filtered and suctioned to afford the white solid product (0.3509 g). Yield: 93.3%, mp 265–268° C. DEC.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=1.O.Cl>C(OCC)C.C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:11]([OH:16])([CH3:1])[C:12]([F:14])([F:15])[F:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cccc(Br)c1)C(F)(F)F
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)(c1cccc(Br)c1)C(F)(F)F

Procedure:
Under argon and with stirring, 22.7 ml (22.7 mmol) of a 1 M solution of methylmagnesium bromide in diethyl ether were added dropwise at 0° C. to a solution of 5.22 g (20.6 mmol) of 1-(3-bromophenyl)-2,2,2-trifluoroethanone in 40 ml of anhydrous THF. After the addition had ended, the reaction mixture was stirred at 0° C. for another 30 min. Then—still at 0° C.—excess Grignard reagent was hydrolyzed by careful addition of water. The mixture was then adjusted to a pH of about 5 by addition of 2 M hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with in each case about 20 ml of diethyl ether. The combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness on a rotary evaporator. This gave 5.32 g (95% of theory) of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=O)[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)=[CH:9][CH:8]=1.C(#[N:25])C>O>[NH2:25][C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: O=C(O)c1cc(=O)[nH]c(-c2ccc(Cl)cc2)n1
Reactant: CC#N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1cc(C(=O)O)nc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To phosphorus oxychloride (180 mL) was added 2-(4-chlorophenyl)-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A) (81.81 g, 326 mmol). The mixture was heated to 90° C. for 2.5 h. After cooling to room temperature the reaction mixture was slowly added to 1:2 acetonitrile:water (1.5 L) while keeping the temperature between 35 and 45° C. After the reaction mixture was stirred at room temperature for 30 minutes the resulting solid was isolated by filtration and washed with water. The solid was then combined with aqueous ammonia (5%, 2.1 L) and heated to 80° C. for 18 h. After 2 days at room temperature the solid was isolated by filtration and washed with water. A second crop was obtained by cooling the filtrate and refiltering. The combined solids were dried to afford the title compound (58.8 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:15])[C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:16][CH2:17]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C1COCC1>[Cl:16][CH2:17][C:10](=[O:12])[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:15]
Reactant: CCOC(=O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])CCl
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A mixture of 5.00 g (21.52 mmol) of ethyl (R)-2-(tert-butyldimethylsilyloxy)propionate, 3.76 g (32.3 mmol) of sodium chloroacetate, 2.18 g (21.5 mmol) of triethylamine, and 50 mL of THF was cooled in ice, and 37 mL (64.6 mmol) of a 1.75 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 1 hour. After the completion of the dropwise addition, the reaction was allowed to proceed at 0° C. for 3 hours, and 6 M hydrochloric acid (about 20 mL) was added to the reaction solution to adjust the pH to 6.0. Subsequently, stirring was performed at 25° C. for 2 hours. A product was extracted with ethyl acetate (100 mL×2). The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.19 g of the title compound as a colorless oil (yield: 100%). 1H-NMR (400 MHz, CDCl3) δ: 0.10 (S, 6H), 0.92 (s, 9H), 1.24 (d, 3H, J=6.8 Hz), 4.35 (q, 1H, J=6.8 Hz), 5.50 (q, 2H, J=17.0 Hz).