Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:12]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH2:25]([CH:24]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[OH:2])=[N:12]1)[CH2:27][CH3:28])[CH3:26]
Reactant: CCC(CC)n1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCC(CC)n1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Yield: 70.9 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-1-(1-ethylpropyl)-7-(trifluoromethyl)-1H-indazole (0.557 g, 1.42 mmol), boron tribromide (0.81 mL, 8.51 mmol) and 0.5 mL of cyclohexene to give the product (0.367 g) as an off-white solid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([OH:28])=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][C:32]1[C:37]([CH2:38]O)=[CH:36][CH:35]=[C:34]([C:40]([F:43])([F:42])[F:41])[N:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([O:28][CH2:38][C:37]3[C:32]([CH3:31])=[N:33][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:35][CH:36]=3)=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1csc2c(F)c(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(F)c(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of tri-n-butylphosphine (0.264 mL), methyl(4-chloro-7-fluoro-6-hydroxy-1-benzothiophen-3-yl)acetate (116 mg), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (89 mg) and THF (4.0 mL) was added ADDP (213 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated in vacuo. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (172 mg).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]([Cl:28])=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[N:20]2)=[CH:15][CH:14]=1)[CH3:9])C.[OH-].[Na+]>CCO.O>[Cl:28][C:27]1[N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][N:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:18][CH:17]=2)[N:20]=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: CCOC(=O)CCCN(C)CCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(CCCC(=O)O)CCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 53.8 %

Procedure:
A solution of this ester from step 1 (0.1 g, 0.23 mmol) and NaOH (20 mg, 0.47 mmol) in EtOH/water (1.1, 5 mL) was stirred at room temperature for 16 h. After the ethanol was removed, the aqueous solution was acidified with 10% HCl to pH=2, extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The crude material was triturated with ether to yield the title compound (48 mg, 50%); 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.01 (d, J=9.2 Hz, 2H), 7.76 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.30 (m, 1H), 7.15 (d, J=8 Hz, 2H), 7.08 (m, 1H), 4.15 (t, J=12, 6 Hz, 2H), 3.27 (m, 4H), 2.84 (m, 2H), 2.76 (s, 3H), 2.18 (m, 2H); LC/MS (ESI+) m/z: 98%.
Reaction SMILES: [CH:1]([C@H:4]1[NH:19][C:18](=[O:20])[C@@H:17]([CH2:21][S:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:16][C:15](=[O:42])[C@@H:14]([CH:43]([CH3:45])[CH3:44])[NH:13][C:12](=[O:46])[CH2:11][C@@H:10](/[CH:47]=[CH:48]/[CH2:49][CH2:50][S:51]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:9][C:8](=[O:71])[CH2:7][NH:6][C:5]1=[O:72])([CH3:3])[CH3:2]>C(Cl)Cl.CO>[CH:1]([C@H:4]1[NH:19][C:18](=[O:20])[C@@H:17]2[NH:16][C:15](=[O:42])[C@@H:14]([CH:43]([CH3:45])[CH3:44])[NH:13][C:12](=[O:46])[CH2:11][C@@H:10]([CH:47]=[CH:48][CH2:49][CH2:50][S:51][S:22][CH2:21]2)[O:9][C:8](=[O:71])[CH2:7][NH:6][C:5]1=[O:72])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC(=O)[C@@H](C(C)C)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC1=O
Agent: CC(C)[C@H]1NC(=O)C[C@H]2/C=C/CCSSC[C@@H](NC1=O)C(=O)N[C@H](C(C)C)C(=O)NCC(=O)O2
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)C[C@H]2C=CCCSSC[C@@H](NC1=O)C(=O)N[C@H](C(C)C)C(=O)NCC(=O)O2

Procedure:
To a vigorously stirred solution of 12 (305 mg, 1.2 mmol) in CH2Cl2/MeOH (9:1, 280 mL) was added dropwise a solution of bis-trityl 8C (120 mg, 0.12 mmol) over 30 minutes. After a further 30 min the reaction was quenched by the addition of sodium thiosulfate (0.05M, 100 mL) followed by brine (10 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give a white solid. Purification by column chromatography on silica gel (1-4% MeOH/CH2Cl2) gave bicyclic depsipeptide 9C (60 mg, 0.12 mmol, 97%) as a white solid: [α]25D −105.7 (1:1 MeOH/CHCl3, c 0.15); 1H-NMR (400 MHz, CD3OD) δ 5.76-5.63 (m, 3H), 4.52 (dd, J=11.3, 4.7 Hz, 1H), 3.96 (d, J=5.1 Hz, 1H), 3.74 (d, J=17.5 Hz, 1H), 3.38 (d, J=10.9 Hz, 1H), 3.19-3.11 (m, 2H), 3.09-2.96 (m, 3H), 2.90 (dd, J=13.6, 2.5 Hz, 1H), 2.71-2.62 (m, 2H), 2.58-2.44 (m, 1H), 2.31-2.18 (m, 1H), 1.11 (d, J=7.0 Hz, 3H), 1.09 (d, J=7.0 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H); 13C-NMR (100 MHz, CD3OD) δ 171.8 (C), 171.7 (C), 170.7 (C), 170.4 (C), 168.3 (C), 130.0 (CH), 129.6 (CH), 69.8 (CH), 64.6 (CH), 61.9 (CH), 54.8 (CH), 42.2 (CH2), 39.3 (CH2), 37.5 (CH2), 37.1 (CH2), 32.1 (CH2), 29.2 (CH), 27.3 (CH), 20.6 (CH3), 20.0 (CH3), 19.4 (CH3), 19.0 (CH3); LRMS (ES+) m/z 537 (100%, [M+Na]+), 515 (90%, [M+H]+).
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:18][C:19](=[CH2:27])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:19]([CH3:27])([CH3:18])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(O)cc1
Reactant: C=C(C)CCCC(=O)OC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc(O)c(C(C)(C)CCCC(=O)OC)c1

Procedure:
2.3 Parts of 4-n-decylphenol, 1.4 parts of methyl 5-methyl-hex-5-enoate, 0.25 of 70% perchloric acid, and 10 parts of methylene chloride were stored for 12 days at room temperature. The work up followed Example 61 and gave on distillation, methyl 5-(5-n-decyl-2-hydroxyphenyl)-5-methyl-hexanoate, b0.8, 160°-7° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]1[CH:27]([C:28]([OH:30])=O)[CH2:26][S:25][CH:24]1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[C:37]1([NH:43][NH2:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[C:37]1([NH:43][NH:44][C:28]([CH:27]2[CH2:26][S:25][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:23]2[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])=[O:30])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NNc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(C(=O)NNc2ccccc2)CSC1c1cccnc1
Reaction time: 12 h
Yield: 95.7 %

Procedure:
A solution of 450 mg of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 680 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid, 240 mg of phenylhydrazine, 450 mg of 1-hydroxybenzotriazole and 20 ml of tetrahydrofuran with ice cooling, and the resultant mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate Concentration under reduced pressure gave 840 mg of N'-phenyl-3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carbohydrazide. Trifluoroacetic acid (5 ml) was added to the thus-obtained compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate Concentration under reduced pressure gave crystals, which were recrystallized from ethyl acetate. Thus was obtained 180 mg of N'-phenyl- 2-(3-pyridyl)thiazolidine-4-carbohydrazide. Melting point 155° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([O:62][Si](C(C)(C)C)(C)C)[CH3:61])=[CH:54]4)[CH:46]([OH:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:71])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([OH:62])[CH3:61])=[CH:54]4)[CH:46]([OH:70])[CH2:45]2)[CH:7]([CH3:72])[CH:6]([OH:73])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O[Si](C)(C)C(C)(C)C)cc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O)cc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-t-butyl-dimethylsilyloxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (74mg) in CH2Cl2 (2 mL.) at rt was added a solution of p-toluene sulfonic acid (10 mg.) in CH3OH (2 mL.). The reaction mixture was stirred for 3 hr., quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 44.8 mg of the title compound. Partial 1H NMR (CDCl, 200 MHz) d: 7.24 (d, J=9 Hz, 1H); 7.15 (d, J=3 Hz, 1H); 7.12 (d, J=3.5 Hz, 1H); 6.86 (dd, J=3 and J=9 Hz, 1H); 6.39 (d, J=3.5, 1H); 4.20 (t, J=5, 2H).
Reaction SMILES: C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C.[Br:49][C:50]1[N:51]2[C:56]3[N:57]4[CH2:86][CH2:85][C:60]([CH3:87])([O:61][CH2:62][CH2:63][CH2:64][CH2:65][C@H:66]([CH3:84])[O:67][C:68]5[CH:69]=[C:70](C)[C:71]([F:82])=[CH:72][C:73]=5[C:74]5[CH:81]=[C:78]([C:79]=1[N:80]=[C:52]2[CH:53]=[C:54]([CH3:98])[C:55]=3[C@H:88]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])[C:89]([O:91][CH3:92])=[O:90])[CH:77]=[CH:76][CH:75]=5)[CH2:59][CH2:58]4>>[Br:49][C:50]1[N:51]2[C:56]3[N:57]4[CH2:58][CH2:59][C:60]([CH3:87])([O:61][CH2:62][CH2:63][CH2:64][CH2:65][C@H:66]([CH3:84])[O:67][C:68]5[CH:69]=[CH:70][C:71]([F:82])=[CH:72][C:73]=5[C:74]5[CH:81]=[C:78]([C:79]=1[N:80]=[C:52]2[CH:53]=[C:54]([CH3:98])[C:55]=3[C@H:88]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])[C:89]([O:91][CH3:92])=[O:90])[CH:77]=[CH:76][CH:75]=5)[CH2:85][CH2:86]4
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 87 %

Procedure:
Prepared in 87.0% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-[(22S)-8-bromo-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 736.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[CH3:22][S:23](C1C=CC(CC(C(O)=O)C(O)=O)=CC=1)(=[O:25])=[O:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: CS(=O)(=O)c1ccc(CC(C(=O)O)C(=O)O)cc1
Product: CS(=O)(=O)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(4-methylsulfonylbenzyl)malonic acid (Intermediate 8: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH:16]3[CH2:21][CH2:20][C:19](=[CH:22][O:23]C)[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH:22]=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC=C1CCC(C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A solution of 0.95 g of 4'-fluoro-4-[[4-(methoxymethylidene)cyclohexyl]ethynyl]biphenyl in 40 ml of toluene was treated with 4 ml of formic acid and stirred at room temperature overnight. The formic acid phase was separated and the toluene phase was washed neutral with water, dried over sodium sulphate, filtered and concentrated. For the ring isomerization, the resulting crude 4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanecarboxaldehyde was dissolved in 35 ml of ethanol, treated with 8.2 ml of 0.1N alcoholic potassium hydroxide solution and stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, washed with saturated sodium hydrogen carbonate solution and with water, dried over sodium sulphate, filtered and concentrated. 0.80 g of trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanecarboxaldehyde was obtained.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][NH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10].CI.O>CN(C=O)C.CCOC(C)=O>[CH3:7][O:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][N:16]([CH3:1])[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc2c1OCCN2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1OCCN2C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
K2CO3 (4.76 mmol) is added to a solution of 3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid methyl ester (2.07 mmol) in DMF (3.0 mL). After 30 min methyl iodide (4.14 mmol) is added and the mixture is stirred for 2 h at 75° C. Cold water and EtOAc are added, the layers are separated and the aq. layer is extracted with EtOAc. The combined organic layers are washed with water and brine, dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.83 min; [M+H]+=208.1.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[CH3:27])[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[CH3:27])[N:13]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(C)c1

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.4 mmol) in toluene (3 mL) was added 4-methoxy-2-methyl-benzyl chloride (0.9 mmol) and cyanomethylene-tri-n-butylphosphorane (1 mmol). The mixture was heated at 110° C. for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained (54 mg). The other regioisomer, 3-(4-chloro-phenyl)-2-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, was also obtained (86 mg). 3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (20 mg) was treated with TFA (1 mL) in CH2Cl2 (10 mL) for 4 h. After concentration of the reaction mixture, the title compound was obtained (0.02 g). MS (ESI): exact mass calculated for C22H24ClN3O, 381.16. found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.34-7.32 (m, 2H), 6.68-6.66 (br m, 1H), 6.54-6.52 (br m, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.21 (s, 2H), 2.81-2.79 (m, 4H), 2.71-2.69 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[O:31]=[S:26]1(=[O:32])[CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 86.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 211 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (386 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][C:14](=[C:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CCO.[Pd]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)C(C)=C1CCN(c2ncc([N+](=O)[O-])cc2C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)C1CCN(c2ncc(N)cc2C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Ethyl 2-[1-(3-methyl-5-nitropyridin-2-yl)piperidin-4-ylidene]propanoate (2.30 g; 7.20 mmol) was suspended in EtOH (100 mL) and treated with 10% Pd/C (230 mg). The resulting mixture was placed under an atmosphere of hydrogen (balloon) at ambient temperature and stirred vigorously at ambient temperature for 2 hrs. LCMS indicated no reduction of alkene but reduction of the nitro-group was essentially complete. The catalyst was filtered off and the filtrate was evaporated to a gum (2.42 g). The reaction was repeated under 20 bar of hydrogen, at 30° C., for 3 hrs with 241 mg 10% Pd/C catalyst. The catalyst was filtered off (Celite) and the solvent removed under vacuum to leave a dark blue gum (2.12 g). This was used in the next step without further purification. 1H NMR δ 1.06 (d, 3H), 1.18 (t, 3H), 1.24-1.43 (m, 2H), 1.45-1.63 (m, 2H), 1.61-1.74 (m, 1H), 2.06 (s, 3H), 2.21-2.35 (m, 1H), 2.50-2.63 (m, 1H), 2.99-3.13 (m, 2H), 3.36-3.50 (m, 1H), 3.98-4.14 (m, 2H), 4.65 (s, 2H), 6.76 (d, 1H), 7.47 (d, 1H). MS m/e MH+ 292.27.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOCCOC1.[CH3:21][C:22]([CH3:50])([CH3:49])[CH2:23][N:24]1[C:28]2[N:29]=[C:30]([C:33]#[N:34])[N:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[CH2:35][N:36]1[C:40](=[O:41])[C:39]2([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[N:38]([CH3:47])[C:37]1=[O:48].Br[CH2:52][CH2:53][CH3:54]>CN(C=O)C>[CH3:21][C:22]([CH3:50])([CH3:49])[CH2:23][N:24]1[C:28]2[N:29]=[C:30]([C:33]#[N:34])[N:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[CH2:35][N:36]1[C:40](=[O:41])[C:39]2([CH2:42][CH2:43][N:44]([CH2:52][CH2:53][CH3:54])[CH2:45][CH2:46]2)[N:38]([CH3:47])[C:37]1=[O:48]
Reactant: CCCBr
Reactant: CN1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C12CCNCC2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC2(CC1)C(=O)N(Cc1cc3cnc(C#N)nc3n1CC(C)(C)C)C(=O)N2C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
To a suspension of 27.4 mg (0.685 mmoles) of NaH and 6.5 mg (0.025 mmoles) of 18-crown-6 in 2.0 ml of DMF, 200 mg (0.488 mmoles) of 7-(2,2-Dimethyl-propyl)-6-(1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile is added at ambient temperature. After being stirred for 10 minutes, 75□l (0.823 mmoles) of 1-bromo propane is added at 0° C. and the reaction mixture is stirred for 5 hours at ambient temperature. The reaction mixture is quenched with cold H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated reduced pressure. The residue is purified by silica gel column chromatography to give 90.5 mg of desired 7-(2,2-dimethyl-propyl)-6-(1-methyl-2,4-dioxo-8-propyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 41% yield.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15].[OH-].[K+:20]>CO>[O:15]=[C:14]([CH:16]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:13]([O-:18])=[O:17].[K+:20]
Reactant: O=CC=CC=Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=CC=CC=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 5-phenyl-2,4-pentadienal (6.70 g) and pyruvic acid (3.0 mL) in 5 mL of methanol was stirred and chilled to 0 -5° C. in an ice bath. To the chilled solution was added a solution of 35 mL of potassium hydroxide (3.5 g) in 10 mL of methanol dropwise over a period of 30 minutes. The remaining methanolic potassium hydroxide was added rapidly and the ice bath was removed. The reaction was allowed to warm to room temperature and stirred for another hour. The flask was then refrigerated overnight. The solid was collected by filtration, washed with 15 mL of methanol three times, 15 mL of ether and then air dried to afford 6.69 g of potassium 2-oxo-8-phenyl-3,5,7-octatrienoate as a yellow solid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.52 (d, 2H), 7.32 (m, 3H), 7.10 (m, 2H), 6.83 (dd, 2H), 6.57 (dd, 1H), 6.13 (d, 1H).