Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:23]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:34][C:35]1[CH:36]=[C:37]([CH:41]2[CH2:46][CH:45]([O:47][CH3:48])C[CH2:43][O:42]2)[CH:38]=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH3:43][O:42][C:41]1([C:37]2[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=2)[O:34][C:2]2[O:3][C:4]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH2:46][CH2:45][O:47][CH2:48][CH2:23]1
Reactant: CN(C)C=O
Reactant: COC1CCOC(c2cccc(O)c2)C1
Reactant: NS(=O)(=O)c1ccc(-c2oc(Cl)nc2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC1(c2cccc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Yield: 44 %

Procedure:
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Example 4, Step 3, (0.6 g, 1.8 mmol), DMF (20 mL), potassium carbonate (0.5 g, 3.6 mmol), and 4 (3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (0.37 g, 1.8 mmol) [prepared as described by G. C. Crawley, et al, J. Med. Chem., 35, 2600-2609 (1992)] were stirred at room temperature for 16.0 hours. The solution was diluted with ethyl acetate (100 mL) , washed with 1N HCl, brine and water, dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and the residue recrystallized from ethyl acetate/hexanes to give 4-[2-[3-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide as a white solid (0.4 g, 44%): mp 145-147° C. 1H NMR (CDCl3) 300 MHz δ 7.88 (d, J=8.9 Hz, 2H) 7.70 (d, J=8.9 Hz, 2H) 7.6 (m, 2H) 7.36-7.5 (m, 6H) 7.0-7.1 (dt, J=6.4 Hz and J=2.2 Hz, 1H) 4.85 (bs, 2H) 3.7 (m, 4H) 3.05 (s, 3H) 2.0 (m, 4H). Final. Calc'd. for C27H26N2O6S: C, 64.02; H, 5.17; N, 5.53. Found: C, 63.94; H, 5.17; N, 5.55.
Reaction SMILES: C([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(O)=O.N1C2C(=CC=CC=2)C=CC=1>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:19][N:6]1[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[C:8]([CH3:9])[CH:4]=[C:5]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cc1c(C(=O)O)c(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C)cc2)n1C
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
A solution of 33.0 g. (0.096 mole) of ethyl 3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 200 ml. of quinoline with 0.1 g. copper chromite added is heated under nitrogen for 6 hours at 200° C., then for 30 minutes at 220° C. The quinoline is distilled off in vacuo. The residue is dissolved in ether and washed successively with dilute hydrochloric acid, dilute sodium hydroxide, and brine; dried over magnesium sulfate; and the solvent evaporated in vacuo to give a brown oily residue which crystallizes. It is recrystallized from methanol, sublimed at 150° C. (0.025 mm/Hg) and recrystallized from hexane to give ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate as a white solid, m.p. 90-93° C.
Reaction SMILES: O=[C:2]1[O:7][CH:6]=[C:5]([C:8]([O-:10])=[O:9])[CH:4]=[CH:3]1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:18]O>>[CH:11]1([N:17]2[C:2](=[O:7])[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:18])=[O:9])=[CH:6]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])c1ccc(=O)oc1
Reactant: CO
Reactant: NC1CCCCC1
Product: COC(=O)c1ccc(=O)n(C2CCCCC2)c1
Yield: 26 %

Procedure:
To a solution of 6-oxo-6H-pyran-3-carboxylate (1.14 g, 7.4 mmol, Aldrich) and 20 mL of MeOH was added cyclohexylamine (2.50 mL, 21.9 mmol, Aldrich). The solution was stirred at reflux for 16 hours, then concentrated in vacuo. The crude material was chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 5% to 20% EtOAc:hexane to give 460 mg (26%) of the title compound as a dark yellow oil. MS m/z: 236.4 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]([N:8]1[C:12](=O)[CH2:11][S:10][C:9]1=[O:14])=[O:7].[H-].[Na+].C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](=[O:39])[CH2:35][N:36]=[C:37]=[O:38])=[CH:26]1)=O)(C)(C)C.C1C[O:43]CC1>>[CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]([N:8]1[CH:12]=[C:11]([O:43][C:37](=[O:38])[NH:36][CH2:35][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][CH:26]=2)=[O:39])[S:10][C:9]1=[O:14])=[O:7]
Reactant: C1CCOC1
Reactant: CC(C)=CCNC(=O)N1C(=O)CSC1=O
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)CN=C=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCNC(=O)n1cc(OC(=O)NCC(=O)c2c[nH]c3ccccc23)sc1=O

Procedure:
To a stirred solution of 3-(3-methyl-but-2-en-1-yl)aminocarbonyl-2,4-thiazolidinedione (0.01 mol), which may be prepared as described in Step (a) above, in a solvent such as, for example, THF is added 1 mol equivalent of a non-nucleophilic base such as described in Step (f) above, preferably sodium hydride, and the mixture is stirred for from 1 minute to about 1 hour. To the mixture is added a solution of 2-(1-tert-butoxycarbonyl-indol-3-yl)-2-oxo-ethylisocyanate (0.01 mol), which may be prepared as described in Step (f) above, in a solvent such as, for example, THF. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of desired product is formed, the mixture is partitioned between ethyl acetate and water, or optionally the mixture is first rotary evaporated, and the residue is so partitioned. The organic layer is washed with 0.01 M hydrochloric acid, water, brine, and dried over sodium sulfate. The mixture is rotary evaporated to give 2-[1-(tert-butoxycarbonyl)-indol-3-yl)-2-oxo-ethyl]carbamic acid, [3-(3-methyl-but-2-en-1-yl)aminocarbonyl-2,3-dihydrothiazol-2-on-5-yl] ester, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[CH:12][C:4]=2[CH:3]=1.[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:23][CH2:22]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:27]=[C:28]([F:42])[C:29]([CH3:41])=[C:30]([C:2]3[C:7](=[O:8])[N:6]([CH3:9])[C:5]4[N:10]([C:13]5[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=5[F:20])[N:11]=[CH:12][C:4]=4[CH:3]=3)[CH:31]=2)[CH2:22][CH2:23]1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 130 °C
Yield: 66.3 %

Procedure:
A mixture of 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (110 mg, 0.32 mmol), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (122 mg, 0.38 mmol) and 15 mg of Pd(PPh3)4 in 2.0 mL dioxane and 0.8 mL of 1 M Na2CO3 in a sealed glass tube was heated at 130° C. for 30 min. The reaction mixture was diluted in EtOAc, washed with 1 N NaOH solution. The organic phase was dried over MgSO4, filtered and concentrated. Purification of the brown residue on an ISCO 12 g column (40-80% EtOAc in Hexanes) afforded the title compound (96 mg) as an off white amorphous solid. MS (ESI, pos.ion) m/z: 453.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[CH3:45][NH:46][CH2:47][C:48]#[N:49].CN1CCOCC1>CN(C=O)C>[C:48]([CH2:47][N:46]([CH3:45])[C:13](=[O:15])[C@H:12]([N:9]1[C:8](=[O:19])[C:7]2=[CH:20][NH:21][C:5]3[C:6]2=[C:11]([C:2]([F:1])=[CH:3][N:4]=3)[CH2:10]1)[CH:16]([CH3:18])[CH3:17])#[N:49]
Reactant: CNCC#N
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N(C)CC#N)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 2-(Methylamino)acetonitrile (5.41 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-55% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a pale yellow solid (7.8 mg, 44%). 1H NMR (500 MHz, DMSO-d6) δ 0.78 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H), 2.44-2.51 (m, 1H), 3.12 (s, 3H), 4.39 (AB q, J=84.5, 17.5 Hz, 2H), 4.89 (d, J=5.5 Hz, 2H), 5.42 (d, J=11.0 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.43 (s, 1H). [M+H] calc'd for C17H18FN5O2, 344; found, 344.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1.[N+:21]([O-])([O-:23])=[O:22].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C>[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc(N)c2c1OCCO2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Concentrated sulphuric acid (6.5 ml) was treated cautiously with stirring at 5°-10° C. with glacial acetic acid (12 ml) and to the resulting solution was added methyl 8-amino-1,4-benzodioxan-5-carboxylate (1.5 g, 0.0072 mole). The mixture was stirred at room temperature for 1 h, then treated portionwise over 45 minutes with potassium nitrate (0.85 g, 0.0084 mole). The mixture was stirred for a further 4 h then poured into water (100 ml) and basified with potassium carbonate. A precipitate was produced and this was filtered off, washed with water and dried to afford methyl 8-amino-7-nitro-1,4-benzodioxan-5-carboxylate as a yellow solid (0.30 g). The filtrate was extracted with ethyl acetate and the extract dried (Na2SO4) and concentrated in vacuo to afford a further 1.1 g of the product as an orange solid. 1H NMR (CDCl3) δ:8.50(s,1 H), 6.0-7.0(v br,2 H), 4.30-4.55(m,4 H), 3.87(s,3 H).
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]([O:11][C:12]([N:14]=[C:15]=[O:16])=[O:13])[CH3:10]>C(N(CC)CC)C.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[O:16])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOC(=O)N=C=O
Reactant: CCOP([O-])OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=O)P(=O)(OCC)OCC

Procedure:
To a solution of 11.0 parts of diethylphosphite in 175 parts of methylene chloride and 4 drops of triethyl amine was added 10.0 parts of ethoxycarbonyl isocyanate. The solution was refluxed for 3 hours. Removing the solvent under reduced pressure left 18.5 parts of colorless oil which partially crystallized. The crystals were washed with cyclohexane to give 7.3 parts of ethyl N-(diethylphosphonocarbonyl)carbamate, m.p. 57°-64°, The proton nmr spectrum was consistent with this structure. (δNH = 10.0 ppm)
Reaction SMILES: ClC1C=C(C2O[C:11]([C:23]([N:25]3[CH2:29][C:28](=[O:30])NC3)=O)=CC=2C2C=C(C#N)C=C(F)C=2)C=CC=1F.[C:31]([C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[C:42]([C:53](OCC)=[O:54])[O:43][C:44]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]#[N:52])[CH:46]=2)[CH:36]=[C:37]([F:39])[CH:38]=1)#[N:32]>>[C:51]([C:47]1[CH:46]=[C:45]([C:44]2[O:43][C:42]([C:53]([N:25]3[CH2:23][CH2:11][O:30][CH2:28][CH2:29]3)=[O:54])=[CH:41][C:40]=2[C:35]2[CH:34]=[C:33]([C:31]#[N:32])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH:50]=[CH:49][CH:48]=1)#[N:52]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2cccc(C#N)c2)o1
Reactant: N#Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)oc2-c2ccc(F)c(Cl)c2)c1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)N3CCOCC3)oc2-c2cccc(C#N)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 31 starting with the compound from Example 17A. 32.1 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: Cl[CH:2]1[N:7](Cl)[CH:6]=[CH:5][C:4]([Cl:9])=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].[SH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:23][C:24]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>C(O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][S:16][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:24]=2[CH3:23])[N:7]=1)[CH3:22]
Reactant: ClC1=NC(Cl)N(Cl)C=C1
Reactant: CCOC(=O)CS
Reactant: Cc1cccc(N)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1cc(Cl)nc(Nc2cccc(C)c2C)n1
Reaction time: 8 h

Procedure:
A mixture of 18.3 g. of 2,3,6-trichloropyrimidine, 10.6 g. of sodium carbonate and 12.0 g. of ethyl mercaptoacetate in 250 ml. of ethanol was heated with stirring under reflux for 3 hours. 2,3-Dimethylaniline (12.2 g.) was added and refluxing with stirring was continued overnight. The reaction mixture was filtered and the filtrate taken to dryness on a rotary evaporator. The residual oil was dissolved in 100 ml. of ethyl acetate and the resulting solution was diluted to 250 ml. with petroleum ether. There was obtained 5 g. of product. Recrystallization from heptane gave 3.8 g. of pure product, mp. 114°-116°C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:15]=3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[F:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:15]=3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazine (54 mg, 0.12 mmol) in a mixture of THF (2.0 mL) and MeOH (2.0 mL) were added NH4Cl (127 mg, 2.4 mmol) and Zn dust (78 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 h, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to provide the desired product (40 mg, 82% yield). MS(ESI) m/z 407.19 (M+H)+.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16](O)=O)=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C([O:47][C:48](=[O:58])CCSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][CH2:16][C:48]([OH:58])=[O:47])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)C1CCC(NC2CCCCC2)CC1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cyclohexyl-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].[K+]>CO.[Pd]>[C:16]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18][C:13]([N:4]2[N:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: O=c1c2ccccc2c(O)nn1-c1ccc(-c2ccccc2)cc1
Yield: 74.2 %

Procedure:
4-Hydroxy-2-(4-iodophenyl)-2H-phthalazin-1-one (0.1 g, 0.3 mmol), phenyl boronic acid (0.04 g, 3 mmol), palladium black (0.02 g, 0.2 mmol) and KF (0.1 g, 18 mmol) were dissolved in MeOH (2 ml) and heated at reflux for 7 h. Removal of supernatant palladium by filtration, extraction with H2O and subsequent filtration of the precipitated solid yielded the desired title compound (0.07 g, 78% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.88 (1H, s), 8.33 (1H, d), 7.89–8.03 (3H, m), 7.78–7.86 (6H, m), 7.50 (2H, t), 7.39 (1H, t),; MS (ESI+)=315.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.[CH2:20]([Li])CCC.CI.O>CCCCCC>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH:8]([CH3:20])[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CCN2c3ccccc3Cn3cccc3C2C1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: O
Product: CC1c2ccccc2N2CCN(C)CC2c2cccn21

Procedure:
To the solution of 2.5 g of 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (Example 1) in 25 ml of tetrahydrofran is added 4.5 ml of 2.45 molar n-butyl lithium in hexane at room temperature while stirring under nitrogen. The pale yellow solution rapidly becomes cherry-red and the temperature rises about 7°. The mixture is stirred for an additional 45 minutes, whereupon it is treated with methyl iodide until the color of the solution is discharged. After stirring for a further 30 minutes the mixture is poured into 100 ml of water, and the product is extracted with diethyl ether. The extract is washed successively with water and brine, evaporated and the residual oil chromatographed on silica gel, using 2% methanol-methylene chloride as eluent, to yield the 2,10-dimethyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine which is converted to its mono maleate melting at 157°. The identical product is also obtainable according to the methods of Examples 1 and 15 by selecting o-nitro-α-methylbenzyl chloride or bromide respectively.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:17]=[C:16]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1>O1CCOCC1.CCOC(C)=O>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:17]=[C:16]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N)cc1Nc1cccc(C)c1
Reactant: CCN=C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(Nc2cccc(C)c2)c(C(=O)OCC)cn1
Temperature: 100 °C

Procedure:
Ethyl isocyanate (0.898 mL, 1.49 mmol), was added to a solution of compound vi (0.270 g, 0.99 mmol) in 1,4-dioxane (5 mL). The reaction mixture was warmed to 100° C. for 48 h, cooled to room temperature and reduced in vacuo. The resulting orange residue was re-dissolved in EtOAc (15 mL) and reduced in vacuo on to SiO2. Column chromatography (SiO2), eluting with 2:1 Hexanes-EtOAc, gave the desired compound vii. (0.145 g, 0.424 mmol, 43%) as an off-white solid, 1H NMR (300 MHz, DMSO-d6): δ 9.62 (1H, br s), 9.19 (1H, br s), 8.62 (1H, s), 7.85 (1H, br t), 7.31 (1H, t, J 7.7), 7.23 (1H, s), 7.13-7.07 (2H, m), 7.03 (1H, d, J 7.2), 4.31 (2H, q, J 7.2), 3.13 (2H, dq, J 6.7 and 7.2), 2.33 (3H, s), 1.33 (3H, t, J 7.2), 1.05 (3H, t, J 7.2); [M+H]+ m/z=343.1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Cl:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]2)[C:18]1=[O:32].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC>[CH2:5]([O:4][C:2]([N:26]1[C:19]2([C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([CH2:16][C:15]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:13]([Cl:12])[CH:14]=3)[C:18]2=[O:32])[C:29](=[O:30])[NH:28][C:27]1=[O:31])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1NC(=O)C2(C(=O)N(Cc3ccc(Cl)c(Cl)c3)c3ccccc32)N1C(=O)OCc1ccccc1
Reaction time: 72 h
Yield: 64.8 %

Procedure:
A solution of benzyl chloroformate (7.6 g.) in 1,2 dimethoxyethane (50 ml.) was added dropwise to a stirred mixture of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (7.4 g.) and sodium carbonate (8 g.) in 1,2 dimethoxyethane (200 ml.). When the addition was completed the mixture was stirred for 72 hours and then evaporated. The residual solid was dissolved in warm water (300 ml.) and the solution obtained was carefully acidified (concentrated hydrochloric acid) and then extracted with ethyl acetate (3×150 ml.). The combined extracts were washed successively with water (2×200 ml.) and brine (1×200 ml.) and then dried (MgSO4). Evaporation of the solvent gave a buff solid which was recrystallised from ethyl acetate/petrol 60-80 to give 3-benzyloxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (6.5 g.), m.p. 215°-217° C.
Reaction SMILES: FC(F)(F)C(F)(F)C(F)(F)C(OC)=[O:6].S(=O)(=O)(O)O.[CH3:20][C:21]([C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])=[CH2:22]>[Rh]>[CH3:22][C:21]([OH:6])([C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:26])([F:27])[F:28])[CH3:20].[CH3:22][CH:21]([C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:26])([F:27])[F:28])[CH3:20]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=C(C)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Rh]
Agent: O=S(=O)(O)O
Product: CC(C)(O)C(F)(F)C(F)(F)C(F)(F)F
Product: CC(C)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Following the procedure of E. T. McBee et al. ibid, 2-methyl-3,3,4,4,5,5,5-heptafluoro-pentan-2-ol was prepared by adding methyl heptafluorobutyrate to 2 equivalents of methyl Grignard. The alcohol (boiling point 108° C.) was dehydrated with concentrated sulfuric acid to 2-methyl-3,3,4,4,5,5,5-heptafluoro-pent-1-ene (boiling point 55° C.). Hydrogenation of this olefin at 1500 psig using 5% rhodium/carbon gave 2-methyl-3,3,4,4,5,5,5-heptafluoropentane, boiling point 59°-61° C. 1H NMR (CDCl3) δ 1.2 (d, 6 Hz), 2.45 (m). This compound was miscible with silicone oil with a perfluorinated polyether at 25° C. and with light mineral oil at 56° C.