Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:41][CH:42]([F:51])[O:43][C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH2:46]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:46][C:45]4[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=4[O:43][CH:42]([F:41])[F:51])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1OC(F)F
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4OC(F)F)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 45 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) with 2-(difluoromethoxy)aniline yielded the title compound (45% yield) as a pale yellow foam. MS (ISP): m/z=686.5 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:44][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])[CH:19]=2)[C:15]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:16]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3-(methylsulfonyl)phenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-(3-(methylsulfonyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.91 (s, 3 H) 7.57 (dd, J=8.48, 1.49 Hz, 1 H) 7.71 (t, J=7.73 Hz, 1 H) 7.77 (d, J=8.02 Hz, 1 H) 7.84-7.95 (m, 3 H) 8.02 (d, J=7.90 Hz, 2 H) 8.05 (s, 1 H) 8.13 (s, 1 H). m/z (ESI) 448.0 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([NH:29][CH3:30])[C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:33][CH:2]([F:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@H:8]([OH:7])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH:24]([NH:29][CH3:30])[C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: CNC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl-2,2-dimethyl-5-{4-[6-(2,2,2-trifluoro-1-methylamino-ethyl)-pyridin-3-yl]-phenyl}-oxazolidin-3-yl) ethanone (0.12 g, 0.235 mmol) in CH2Cl2 (2 mL) is added trifluroacetic acid (0.5 mL) at 0° C. then is stirred to room temperature for 2 hours. Reaction solvent evaporated in vacuo then diluted with sodium bicarbonate solution and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash eluting in 5% Methanol in CH2Cl2 to afford the title compound (0.028 g). 1H-NMR (400 MHz, DMSO) δ: 2.25 (d, J=5.84 Hz, 3H), 3.00-3.04 (m, 1H), 4.31-4.35 (m, 1.5H), 4.41-4.46 (m, 1.5H), 4.55-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.90 (m, 1H), 5.93 (d, J=4.36 Hz, 1H), 6.19 (d, J=53.72 Hz, 1H), 7.46 (d, J=8.32 Hz, 2H), 7.95-7.98 (dd, J1=1.96HzHz, J2=8.32 Hz, 1H), 8.03 (d, J=8.32 Hz, 1H), 8.06 (d, J=8.48 Hz, 2H), 8.71 (d, J=1.88 Hz, 1H), 8.84 (d, J=8.72 Hz, 1H). LC-MS (m/z): [M+H]=436.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]C)=[O:16])[C:10](=[O:19])[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10](=[O:19])[CH:9]1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1Cc1ccc(OCc2ccccc2)cc1

Procedure:
t-Boc-piperazinoneacetate 4a (0.251 g, 5.37 ×10-4 mole), 1M aqueous LiOH (0.59 ml, 5.9 ×10-4 mole), and methanol (2 ml) are stirred at room temperature for 2 hours. The solvent is then evaporated and the resulting yellow oil is dissolved in CH2Cl2 and transferred to a separatory funnel where it is washed with 0.5M aqueous HCl. The CH2Cl2 layer is separated and the acidic aqueous phase is extracted with CH2Cl2 (3 times). The CH2Cl2 extracts are combined and washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives 5a as a colorless form, which was shown to be homogeneous by TLC on silica gel plates. The structure of 5a was corroborated by NMR. NMR (CDCl3) δ1.27 (S, 9, t-boc), 3.09-4.07 (m, 8, methylenes), 4.68 (t, 1, C3 --H), 4.97 (S, 2, benzyloxy methylene), 6.89 (q, 4, aromatic), 7.30 (S, 5, aromatic), 9.99 (broad S, 1, acid).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@H:35]1[N:40]([CH3:41])[C@@H:39]([CH3:42])[CH2:38][N:37]([CH2:43][CH2:44][OH:45])[CH2:36]1.[OH-].[K+]>CS(C)=O.O>[CH:30]([C:26]1[N:25]=[C:24]([CH2:23][N:18]2[C:19]3[C:15](=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([O:45][CH2:44][CH2:43][N:37]6[CH2:38][C@@H:39]([CH3:42])[N:40]([CH3:41])[C@@H:35]([CH3:34])[CH2:36]6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:33])=[N:17]2)[CH:29]=[CH:28][CH:27]=1)([CH3:32])[CH3:31]
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Reactant: C[C@@H]1CN(CCO)C[C@H](C)N1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5C[C@@H](C)N(C)[C@@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 6.5 %

Procedure:
A pressure tube was charged with 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.500 g, 1.09 mmol), 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol (0.375 g, 2.18 mmol), crushed potassium hydroxide (0.306 g, 5.45 mmol) in 10 mL of DMSO. The tube was sealed and heated to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) followed by trituration with methyl t-butyl ether afforded 42 mgs (6%) of the title compound. MS (APCI), positive scan, m/z=595.1 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=4)=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:30]4[CH:31]=[CH:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=4)=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a solution of 4-{4-[(4′-isopropyl-5-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (4 g) in CH2Cl2 (20 mL) was added trifluoroacetic acid (15 mL) and the solution was stirred at room temperature for 16 hours. The mixture was then evaporated under reduced pressure and the residue was taken in water and basified with a 1N NaOH aqueous solution. The resulting precipitate was extracted with CH2Cl2 and the organic phase was washed with water, dried over Na2SO4 filtered and evaporated to give the title compound (3 g) as white crystals.
Reaction SMILES: C([N:3](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[F:25][C:26]1[C:31]([O:32][CH2:33][CH2:34][F:35])=[CH:30][C:29]([O:36][CH3:37])=[CH:28][C:27]=1[CH:38]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[N:65]=[C:64]([CH3:66])[O:63][N:62]=2)=[CH:57][CH:56]=1)[C:39]1[NH:43][C:42](=[O:44])[N:41]([C:45]2[N:50]=[C:49](C(O)=O)[CH:48]=[CH:47][CH:46]=2)[N:40]=1>O1CCOCC1>[NH2:3][C:49]1[N:50]=[C:45]([N:41]2[C:42](=[O:44])[NH:43][C:39]([CH:38]([C:27]3[CH:28]=[C:29]([O:36][CH3:37])[CH:30]=[C:31]([O:32][CH2:33][CH2:34][F:35])[C:26]=3[F:25])[NH:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]4[N:65]=[C:64]([CH3:66])[O:63][N:62]=4)=[CH:57][CH:56]=3)=[N:40]2)[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3cccc(C(=O)O)n3)c(=O)[nH]2)c1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3cccc(N)n3)c(=O)[nH]2)c1
Temperature: 80 °C

Procedure:
After adding 41 μl of triethylamine and 63 μl of diphenylphosphorylazide to a solution of 81 mg of 6-(3-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)pyridine-2-carboxylic acid in 4 ml of 1,4-dioxane under a nitrogen atmosphere, the mixture was heated for 20 hours at 80° C. After cooling, the reaction mixture was filtered and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (33 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[N:15]([C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:31]2)[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:48](C=O)C>C([O-])(=O)C.[NH4+].C(O)(=O)C.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:29])[F:28])[CH:20]=3)[N:48]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N(CC(=O)c2ccc(F)c(C(F)(F)F)c2)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Yield: 75 %

Procedure:
Heat a solution of 4-{((R)-1-benzyloxycarbonyl-piperidin-3-yl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (4.40 mmol; 2.86 g) in DMF (2.5 mL) and ammonium acetate saturated in acetic acid (15 mL) at 90° C. for 8 h. Dilute with EA, wash the organic phase 3× with water, saturated sodium bicarbonate, brine, dry over MgSO4 and filter. Purify the residue on 80 g silica gel with 5-20% EA/DCM to provide the title compound (2.08 g; 3.30 mmol; 75%). MS (ES+): m/z=631 (M+H).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:23])[C:11]2[C:16]([C:17]=1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl.C(#N)C>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:23])[C:11]2[C:16]([C:17]=1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cncs1
Solvent: ClCCl
Solvent: CC#N
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cncs1
Yield: 44.8 %

Procedure:
1M PBr3 (0.5 ml, 0.50 mmol) in DCM was added drop-wise to of 3-(1-hydroxyethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (Intermediate B11, 102 mg, 0.372 mmol) in DCM (4 ml) and ACN (2 ml) at RT. Reaction mixture was then concentrated under reduced pressure and straightforward purified on Biotage Silica SNAP 12 g cartridge with a gradient of hexane and EtOAc to give the title compound (56 mg, 45%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:12][CH:11]=[N:10][C:9]=2[N:8](COCC[Si](C)(C)C)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.CCOC(C)=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(-c2nccs2)cn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(-c4nccs4)c23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of crude N-(3-(5-(thiazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (38 mg, 0.076 mmol) in DCM (1.0 mL), was added TFA (1.0 mL). The resulting solution was stirred at room temperature for approximately 3 hours before being concentrated in vacuo. The crude residue was then taken up into MeOH (1.0 mL) and ammonium hydroxide (1.0 mL) was added, and the resulting mixture was stirred at room temperature for approximately 30 minutes. The reaction was concentrated to afford a crude solid that was dissolved in a mixture of MeOH and EtOAc, filtered through 2 Stratospheres™ PL-HCO3 MP SPE cartridges, concentrated in vacuo and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophyllization of the desired fractions afforded N-(3-(5-(thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as an off-white solid. LRMS (ESI) calcd for C19H15N5OS [M+H]+: 362, found 362. 1H NMR (600 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.75 (s, 1H), 8.92 (s, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.91 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.55 (m, 2H), 7.07 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 5.74 (s, 1H), 5.47 (s, 1H), 1.90 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[C:16](=[O:17])[N:15]([C@H:18]([C:27](=[O:38])[NH:28][C:29]3[S:30][CH:31]=[C:32]([C:34](=[O:37])[CH2:35][CH3:36])[N:33]=3)[C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:14](=[O:39])[NH:13]2)=[CH:8][CH:7]=1.O.[OH-].[Li+]>O1CCCC1>[O:39]=[C:14]1[NH:13][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:40])=[O:2])=[CH:7][CH:8]=2)[C:16](=[O:17])[N:15]1[C@H:18]([C:27](=[O:38])[NH:28][C:29]1[S:30][CH:31]=[C:32]([C:34](=[O:37])[CH2:35][CH3:36])[N:33]=1)[C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCC(=O)OC)cc3)C2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCC(=O)O)cc3)C2=O)n1

Procedure:
Prepared by hydrolysis of (4-{(R)-2,5-dioxo-1-[(1S,2S)-2-phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propyl]-imidazolidin-4-yl}-phenoxy)-acetic acid methyl ester (prepared as described in example 21) with lithium hydroxide monohydrate in aqueous tetrahydrofuran. Under the conditions employed for the hydrolysis of the methyl ester racemization occurred at the 4-position of the imidazolidinedione ring.
Reaction SMILES: [BrH:1].C(OC(=O)C)(=O)C.Cl.[CH:10]1([NH:16][CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:29]C)[C:23]=3[O:27]C)[C:18]2=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[BrH:1].[CH:10]1([NH:16][CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:29])[C:23]=3[OH:27])[C:18]2=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc2c(c1OC)CCC(NC1CCCCC1)C2=O
Agent: Br
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccc(O)c(O)c2CCC1NC1CCCCC1

Procedure:
In a mixture of 50 volume parts 48 % hydrobromic acid and 15 volume parts acetic anhydride is dissolved 5 parts of 2-cyclohexylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride, and the solution is heated at 140°-160° C for about 3 hours. After cooling, the solvent is removed under reduced pressure and the residue is treated with activated carbon in ethanol. Following the addition of ethyl acetate, the filtrate is allowed to stand, whereby 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide is obtained as colorless prisms. Yield 4.1 parts; melting point: 225°-237° C (decomposition).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CCOCC>[CH2:7]([O:6][C:1](=[O:5])[CH:2]([O:3][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[CH3:4])[CH3:8]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCCCCCCCCCCCI
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(C)C(=O)OCC
Reaction time: 50 h
Yield: 25.7 %

Procedure:
47.0 g of ethyl L-(+)-lactate and 88.4 g of 1-iodododecane were added into a flask and mixed under nitrogen gas stream. 42.1 g of freshly synthesized Ag2O was added in 3 hours. After the mixture was left standing at room temperature for 50 hours, it was heated on a water bath at 60°-70° C. for 4 hours. The mixture was diluted with 200 ml of ether, subjected to filtration and then ether was evaporated. The residue was washed with 100 ml of aqueous 5% KOH, then dried over anhydrous Na2SO4 and subjected to vacuum distillation. The fractions of 169° C./9 mmHg were collected to obtain 22 g of (-)-ethyl-2-dodecyloxypropionate. Optical rotation [α]D23° =-42°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:19])=[O:18]
Reactant: OCCN1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1CCCC1

Procedure:
The 1-(2-hydroxyethyl)-pyrrolidine (Aldrich, 0.14 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[F:47][C:48]([F:64])([F:63])[C:49]1[CH:62]=[CH:61][C:52]([CH2:53][S:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:51][CH:50]=1>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:55]([S:54][CH2:53][C:52]1[CH:51]=[CH:50][C:49]([C:48]([F:47])([F:64])[F:63])=[CH:62][CH:61]=1)[C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CSCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccc(C(F)(F)F)cc1
Yield: 84.9 %

Procedure:
The procedure is as in Example 2, for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5.7 g), a 2M ethanolic solution of sodium ethylate (50 cc) and ethyl (4-trifluoromethylbenzylthio)acetate (5.6 g) in ethanol (50 cc). Diethyl 2-dimethylamino-5-(4-trifluoromethylbenzylthio)-2,4-hexadienedioate (7.3 g) is thereby obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:28]([C:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]#[N:40])=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=O>C(#N)C>[C:39]([C:35]1[CH:34]=[C:33]2[C:38]([C:30](/[CH:28]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:31][NH:32]2)=[CH:37][CH:36]=1)#[N:40]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2c(C=O)c[nH]c2c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1c[nH]c2cc(C#N)ccc12
Reaction time: 3.5 h
Yield: 58.4 %

Procedure:
1,1-Dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1.540 g) was added to a suspension of 3-formyl-1H-indole-6-carbonitrile (D13) (604 mg) in acetonitrile (20 mL) at RT. The reaction mixture was heated to refluxing and stirred for 3.5 hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1 g) was added and the resulting suspension was refluxed for 3 more hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1 g) was added and the resulting suspension was refluxed for 2.5 more hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1 g) was added and the resulting suspension was refluxed for 3 more hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1.5 g) was added and the resulting suspension was refluxed for 3.5 more hours. The solvent was evaporated. The residue was purified by Biotage (33% EtOAc in hexane) to afford 1,1-dimethylethyl (2E)-3-(6-cyano-1H-indol-3-yl)-2-propenoate (D14) as a white solid (556 mg). MS (ES): C16H16N2O2 requires 268; found 267.0 (M−H+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([O:28][CH2:29][CH3:30])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH2:29]([O:28][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:35]4[C:31](=[O:37])[CH2:32][CH2:33][C:34]4=[O:36])[CH2:6][CH2:7]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][CH3:27])[CH3:30]
Reactant: O=C1CCC(=O)N1
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OCC
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-diethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A2) and succinimide as starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
The intermediate from step A (8.8 g, 37.6 mmol) was dissolved in toluene and to it was added PtO2 (0.5 g). The resulting mixture was stirred under hydrogen at atmospheric pressure overnight. The catalyst was filtered off and the filtrate was removed under reduced pressure. Flash chromatography on silica gel eluting with 5% and then 10% EtOAc in hexanes provided the title compound (8.6 g, 98%) as an oil. MS calculated (M+H)+237. Found 237.