Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)([CH2:35][CH3:36])[CH2:33][CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:35][CH3:36])([CH2:37][OH:38])[CH2:33][CH3:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(CC)(CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(C)(C)O[SiH2]C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 94 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-butyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 111b (1.8 g, 2.6 mmol) was reacted trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (1.5 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([NH:6][C@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[CH2:8]2)=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1.C(O[C:26](=[O:28])[CH3:27])(=O)C>N1C=CC=CC=1>[C:11]([O:12][C@@H:11]1[C@H:7]([NH:6][C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[N+:19]([O-:21])=[O:20])[CH2:8][C@H:9]([CH2:14][O:15][C:14](=[O:15])[CH3:9])[C@@H:10]1[O:13][C:26](=[O:28])[CH3:27])(=[O:12])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@@H]1C[C@H](CO)[C@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1C[C@@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 89 %

Procedure:
(1R, 2S, 3R, 5R)-5-(4,5-Dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol (1.30 g, 3.86 mmol) was stirred in pyridine (10 mL)-acetic anhydride (2.2 mL) at ambient temperature for 2 days. Volatiles were evaporated in vacuo and the residue partitioned between chloroform and saturated aqueous sodium bicarbonate. The chloroform layer was dried (sodium sulfate) and concentrated to an oil which was chromatographed on silica gel. Elution with 2% methanol-chloroform gave (1R, 2S, 3R, 5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate as yellow needles (1.60 g, 89%), after crystallization from ethyl acetate-hexanes, m.p. 125°-130° C.; 1H-NMR(DMSO-d6) and mass spectrum (CI) consistent with structure; [α]20589 -130.5°, [α]20578 -140°, [α]20546 -178° (c=0.275, methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 106 %

Procedure:
2-Nitrobenzenesulfonyl chloride (5.79 g) was added to a mixed solution of tetrahydrofuran (20 ml)/water (17 ml) containing (S)-proline (2.00 g), 5 N sodium hydroxide (3.5 ml) and sodium carbonate (3.77 g) under ice cooling, followed by stirring for 1 hour under ice cooling and for 22 hours at room temperature. Water (20 ml) was added to the reaction mixture, and the organic solvent was removed by evaporation under reduced pressure. Then, water (20 ml), 5 N sodium hydroxide (4 ml) and ethyl acetate (100 ml) were added, followed by extraction and solution separation, and the organic layer was extracted again with water (15 ml). Ethyl acetate (50 ml) and 6 N hydrochloric acid (20 ml) were added to the resulting aqueous layer, followed by extraction and solution separation, and the aqueous layer was extracted again with ethyl acetate (50 ml). The resulting organic layer was dried over sodium sulfate, filtered, concentrated and dried under vacuum to obtain (S)-N-(2-nitrobenzenesulfonyl)proline (5.53 g; yield: quantitative).
Reaction SMILES: [NH2:1][C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:4].[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:9][CH2:8]1)=[O:4])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(N)(c2ccccc2)c2ccccc2)CC1
Solvent: ClCCl
Product: CC(=O)NC(C(=O)OCC1CCN(C(=O)OC(C)(C)C)CC1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((2-amino-2,2-diphenylacetyloxy)-methyl)piperidine-1-carboxylate (prepared as in Preparation intermediate 12 with diphenylglycine replacing cyclohexylmandelic acid) (0.50 g, 1.18 mmol) in DCM (1.5 mL) was added a solution of acetic anhydride (0.122 mL, 1.30 mmol) in DCM (0.5 mL). The reaction mixture was heated at 40° C. for 18 hours. The reaction mixture was allowed to cool to RT and further acetic anhydride (0.06 mL, 0.65 mmol) added. The reaction mixture was heated at 40° C. for a further 18 hours. The reaction mixture was allowed to cool to RT, quenched with water, and the mixture was stirred at RT for 1 hour. The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate and DCM. The organic phase was removed and the aqueous phase extracted with further DCM. The combined DCM extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The product was isolated (0.541 g, >100%). The crude product was used without further purification in the next step.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[C:22]([C:23]([O:25]C)=O)=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.[NH4+:28]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[C:22]([C:23]([NH2:28])=[O:25])=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN4CCNCC4)c3)oc12
Reactant: [NH4+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(CN4CCNCC4)c3)oc12
Temperature: 30 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
Methyl 2-(3-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (79 mg, 0.23 mmol) and ammonium water (64.4 mg, 1.84 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide (12 mg, yield 13%). 1H-NMR (400 MHz, DMSO-d6) δ 2.91 (s, 4H), 3.21 (s, 4H), 4.20 (s, 2H), 7.48-7.52 (t, J=8 Hz, 1H), 7.67 (s, 2H), 7.81-7.97 (m, 4H), 8.31 (s, 2H); LC-MS (ESI) m/z 337 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])[C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.[Br:25]N1C(=O)CCC1=O>O1CCCC1>[Br:25][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[N:13]([S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:14]=1
Reactant: Cn1cc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3c(c2)c(Br)cn3S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.832 g, 2.46 mmol) in tetrahydrofuran (12.3 ml) was added N-bromosuccinimide (0.875 g, 4.92 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 10% aqueous sodium thiosulfate solution (50 mL), then extracted with EtOAc (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was adsorbed on to silica gel and purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a white solid. LRMS (ESI) calculated for C17H13BrN4O2S [M+H]+, 417.0; found 417.0.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Si:12]([O:19][CH2:20][CH:21]=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+]>CO>[C:15]([Si:12]([CH3:14])([CH3:13])[O:19][CH2:20][CH2:21][NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[I:1])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc([N+](=O)[O-])cc1I
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2-(tert-butyldimethylsilyloxy)-acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol (30 mL) was added TFA (1.5 mL) at 0° C. The reaction mixture was stirred at this temperature for 30 min before NaCNBH3(900 mg, 15 mmol) was added in portions. The mixture was stirred for 2 h and was then quenched with water. The resulting mixture was extracted with EtOAc (30 mL×3), the combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum, and the residue was purified by chromatography on silica gel (5% ethyl acetate/petroleum) to afford [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-nitro-phenyl)-amine (800 mg, 25%). 1 H NMR (300 MHz, CDCl3) δ 8.57(d, J=2.7 Hz, 1 H), 8.12(dd, J=2.4 ,9.0 Hz, 1 H), 6.49(d, J=9.3 Hz, 1 H), 5.46(br s, 1 H), 3.89(t, J=5.4 Hz, 2 H), 3.35(q, J=5.4 Hz, 2 H), 0.93(s, 9H), 0.10(s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12]O)=[O:4].C([O-])(=O)C.[NH4+:22]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][NH2:22])=[O:4]
Reactant: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C(=CN)c1c(C(=O)OC)ccn1C
Yield: 26.6 %

Procedure:
2-(2-Hydroxy-1-methoxycarbonyl-vinyl)-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (12.46 g), ammonium acetate (20.09 g) and methanol (200 ml) were refluxed under argon for 5 hours. After cooling the solvent was evaporated and the residue dissolved in ethyl acetate and washed with water, the aqueous was separated and extracted three times with ethyl acetate. The combined organics were washed with saturated brine solution and the organic layer was dried (MgSO4), filtered and evaporated. The residue was then taken up in the minimum amount of ethyl acetate and a precipitate formed which was filtered off to yield the title compound as an off-white solid (3.3 g). The filtrate was evaporated to yield the title compound as a brown solid (6.36 g). Both were taken through without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([O:23]CC4C=CC(OC)=CC=4)[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]=[O:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:36]1([C:42]#[C:43][Mg]Br)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>C1COCC1>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([OH:23])[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]([OH:35])[C:43]#[C:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Br[Mg]C#Cc1ccccc1
Reactant: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(C=O)cc2=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(C(O)C#Cc2ccccc2)n(-c2cccc(-c3c(Cl)cnc4[nH]ccc34)c2)cc1O
Reaction time: 0.08 h

Procedure:
To a solution of 0.05 g (0.01 mmol) 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-phenyl]-5-(4-methoxy-benzyloxy)-4-oxo-1,4-dihydro-pyridine-2-carbaldehyde in 3 mL THF at −40° C. was added 1 mL phenylethynylmagnesium bromide (1.0 M in THF). The reaction mixture was stirred at −40° C. for 30 min before 1 mL of water was added. The reaction was gravity filtered through an Isolute HM-N tube, which was rinsed with 4 mL EtOAc and the combined organics were concentrated. The resulting residue was dissolved in 1 mL TFA and allowed to stand at room temperature for 5 min before being concentrated. Purification by automated mass-guided HPLC afforded 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-5-hydroxy-2-(1-hydroxy-3-phenylprop-2-yn-1-yl)pyridin-4(1H)-one. Compound exhibits equilibrating rotational isomerism in solution. Reported NMR data correlates to the major rotational isomer. 1H NMR (500 MHz, CD3OD, 0° C.): δ 8.26 (s, 1H); 7.96 (s, 1H); 7.89-7.78 (m, 3H); 7.71 (t, J=8.59 Hz, 1H); 7.50 (d, J=3.49 Hz, 1H); 7.41-7.36 (m, 5H); 6.34 (d, J=3.46 Hz, 1H); 5.45 (s, 1H). HRMS (FT/ICR) Calc (M+H)+ 468.1109. Found 468.1109.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>O>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)=[CH:13][C:4]1=2)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Solvent: O
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 193-194° C. 1H-NMR (CDCl3) δ9.19 (s, 1H, D2O exchangeable), 8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0 Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H, J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z 325 ([M−H]−, 100%). Anal. Calc. For C18H18N2O4.0.3 H2O: C, 65.17; H, 5.65; N, 8.44. Found: C, 65.31; H, 5.60; N, 8.10.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.[CH2:15]=[O:16]>CC(C)=O>[OH:16][CH2:15][N:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4]1
Reactant: C=O
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(CO)nc1C(F)(F)F
Temperature: 150 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
The mixture of 2.08 g of 3-(trifluoromethyl)-4-ethyoxycarbonyl-1H-pyrazole and 0.66 g of paraformaldehyde was stirred at 150° C. for 4 hours. After the reaction mixture was cooled to room temperature, acetone was added. After the mixture was filtered, the filtrate was concentrated under reduced pressure to obtain 2.23 g of 1-(hydroxymethyl)-3-(trifluoromethyl)-4-ethoxycarbonyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH:13]=[C:12]2[NH:44][C:43]2[CH:45]=[CH:46][C:40]([F:39])=[CH:41][CH:42]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(Nc2ccc(F)cc2)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1

Procedure:
To a solution of 55 mg (0.156 mmol) 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione in 2 mL dry toluene was added 36 mg (0.187 mmol)p-toluenesulfonic acid monohydrate and 0.030 mL (0.312 mmol) 4-fluoroaniline. The reaction mixture was refluxed for 24 hrs. The solvent was then removed by concentration in vacuum. The residue was purified by preparative HPLC (5→95% CH3CN/H2O over 30 min, 0.05% added TFA, C18 PRO YMC 20×150 mm) to afford 8-benzyl-1-(3-fluorophenyl)-4-[(4-fluorophenyl)amino]-1,8-diazaspiro[4.5]dec-3-en-2-one as a white solid. 1H NMR (CD3OD, 400 MHz): δ 7.50-7.20 (m, 7H), 7.20-6.98 (m 6H), 5.24 (s, 1H), 3.60 (s, 2H), 2.99-2.80 (m, 2H), 2.36-2.43 (m, 2H), 2.24-1.98 (m, 2H), 2.10 (m, 1H), 1.00 (m, 2H). High resolution mass spec (FT/ICR): calc M+H=446.2039 found 446.2035.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1([F:21])[CH2:13][CH:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12]2([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C:10]([F:21])([F:9])[CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CC(F)(F)C1
Reactant: Fc1ncccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(c2ncccc2Cl)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.8 %

Procedure:
A solution of 3-chloro-2-fluoropyridine (500 mg, 3.8 mmol) and tert-butyl 3,3-difluorocyclobutanecarboxylate (Preparation 227, 877 mg, 4.6 mmol) in toluene (13 mL) was cooled to 0° C. A solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1M solution in THF, 5.7 mL, 5.7 mmol) was added dropwise. The reaction mixture was stirred for 20 minutes at the same temperature, and then allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with 1N aqueous citric acid solution (3×15 mL), then brine (3×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as yellow oil which was purified by silica gel column chromatography eluting with 0-20% EtOAc in heptane to give the title compound (505 mg, 44%) as colourless oil.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[C:13]([NH:19][CH2:20][C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:14][C:15](F)=[CH:16][CH:17]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:15]1[N:14]=[C:13]([NH:19][CH2:20][C:21]2([C:27]#[N:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:12]([F:11])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#CC1(CNc2nc(F)ccc2F)CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(CNc2nc(OCc3ccccc3)ccc2F)CCOCC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
Benzyl alcohol (352 mg, 3.26 mmol) was dissolved in anhydrous DMF (2 ml) and placed under argon. This was then treated with a 60% dispersion in oil of SODIUM HYDRIDE (78.7 mg, 3.26 mmol). This resultant suspension was then stirred at room temperature for 15 min. At this time it was treated with a solution of 4-((3,6-difluoropyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (275 mg, 1.09 mmol) dissolved in anhydrous DMF (2 ml). Once the addition was complete the reaction was stirred at 90° C. for 5 hours. The reaction was allowed to cool to room temperature. It was then poured into brine (20 ml). This was extracted with EtOAc (3×15 ml). The combined extracts were washed with H2O (3×10 ml) followed by brine (1×10 ml). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo to give the crude material which was purified using the ISCO and a 12 g SiO2 column. Eluted using 100 hexanes to 30 EtOAc/70 hexanes over 20 min. 245 mg (66% yield) of the desired product was obtained as a viscous liquid. LCMS (m/z): 342.1 [M+H]+; retention time=1.017 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3](=[CH2:6])[CH:4]=[O:5].[CH2:8]([O:10][C:11](=[O:15])[CH2:12][N+:13]#[C-:14])[CH3:9]>>[CH2:8]([O:10][C:11]([CH:12]1[CH:4]([C:3]([CH:2]([CH3:7])[CH3:1])=[CH2:6])[O:5][CH:14]=[N:13]1)=[O:15])[CH3:9]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)C(C)C
Product: C=C(C(C)C)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 3-methyl-2-methylene-butanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(3-methyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 15 to 2-formylamino-3-hydroxy-4-isopropyl-4-pentenoic acid ethyl ester. Subsequent treatment with thionyl bromide followed by reaction with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.[O:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:37]4([OH:40])[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4(O)CCOCC4)cc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.60 g, 1.53 mmol) and THF (10 mL) is added 1.56 M n-Bu-Li (1.03 mL, 1.61 mmol). After 30 minutes tetrahydro-pyran-4-one (0.21 mL, 2.29 mmol) is added over 5 minutes. The solution is stirred at −78° C. for 2 hours, warmed to ambient temperature, diluted with EtOAc (50 mL), washed with sat. NH4Cl (50 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-100% EtOAc/hexane gradient) furnish the title compound (0.38 g, 0.92 mmol, 60%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 1.91-2.00 (m, 2H), 2.11 (s, 3H), 2.20-2.30 (m, 2H), 2.46 (s, 3H), 2.51 (s, 3H), 3.30-3.39 (m, 1H), 3.83-3.98 (m, 5H), 6.66 (s, 1H), 6.93 (s, 1H). LC/MS (m/z): calcd. for C23H31N3O2S (M+H)+: 414.3; found: 414.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:6]([CH:8]=1)[NH2:7].[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[C:6]([N:7]=[C:15]=[S:16])[CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(F)ccc1N1CCOCC1
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(N2CCOCC2)c(N=C=S)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 5-fluoro-2-morpholino aniline (6 g) and thiophosgene (5.2 g) in dioxan (20 ml) and water (40 ml) was stirred at 0° C. for 15 minutes and at room temperature for one hour to yield a residue which was extracted with dichloromethane to give an oil which was purified by chromatography on a silica gel column (mesh 100-200) using a 1:9 mixture of ethylacetate and hexane as eluant to give 5-fluoro-2-morpholinophenyl isothiocyanate as an oil.