Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:27]([C:17]34[CH2:26][CH:21]5[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]5)[CH2:24]3)[CH2:18]4)=[O:28])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C12CC3CC(CC(C3)C1)C2)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 150 mg (0.74 mmol) 1-adamantanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80](Cl)[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30](Cl)[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:109][CH2:110][CH2:111][CH2:112][CH2:113][CH2:114][C:115]([O-:117])=[O:116].[Na+]>>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80]([NH:109][CH2:110][CH2:111][CH2:112][CH2:113][CH2:114][C:115]([OH:117])=[O:116])[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30]([NH:109][CH2:110][CH2:111][CH2:112][CH2:113][CH2:114][C:115]([OH:117])=[O:116])[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(N(CCCCCCN(c3nc(Cl)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCCCCC(=O)[O-]
Agent: [Na+]
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(N(CCCCCCN(c3nc(NCCCCCC(=O)O)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-bis{2-chloro-4-[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and sodium 6-aminohexanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:3]=1.[Cl:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:19][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:3]=1
Reactant: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1cc(CCl)ccn1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
A mixture of 2-(4-methyl-pyridin-2-yl)-isoindole-1,3-dione (952 mg, 4 mmol)), N-chloro succinimide (640 mg, 4.8 mmol), and benzoyl peroxide (484 g, 2 mmol) in carbon tetrachloride (20 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, dichloromethane:EA (95:5)) to afford 300 mg (28%) of 2-(4-chloromethyl-pyridin-2-yl)-isoindole-1,3-dione as a pale brown solid. m.p. 152-153° C. 1H NMR (200 MHz, CDCl3) δ 4.64 (2H, s), 7.42 (1H, d, J=5.0 Hz), 7.49 (1H, s), 7.80-7.99 (4H, m), 8.68 (1H, d, J=5.0 Hz).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:12][C@@H:11]1[C@H:20]1[O:24][C:23]([CH3:26])([CH3:25])[N:22]([C:27](=[O:29])[CH3:28])[C@H:21]1[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([CH2:15][C:16]([OH:18])=[O:17])[CH2:12][C@@H:11]1[C@H:20]1[O:24][C:23]([CH3:26])([CH3:25])[N:22]([C:27](=[O:29])[CH3:28])[C@H:21]1[CH2:30][C:31]1[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)CC1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Add LiOH (0.32 mL, 3M solution in water) to a solution of (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-methoxycarbonylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.19 mmol) in 0.32 mL of THF and stir overnight. Remove THF under reduced pressure. Add ethyl acetate and separate the layers. Acidify the aqueous layer with citric acid pH: 3) and extract with ethyl acetate. Dry over MgSO4 and concentrate under reduced pressure to provide the title compound (0.087 g, 90%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[CH2:14][CH3:15].[CH2:17]([NH2:20])[CH2:18][NH2:19]>>[CH2:10]([C:9]1[C:8]([O:12][CH3:13])=[CH:7][CH:6]=[C:5]([CH2:14][CH3:15])[C:4]=1[CH2:3][C:2]1[NH:19][CH2:18][CH2:17][N:20]=1)[CH3:11]
Reactant: CCc1ccc(OC)c(CC)c1C=C(Br)Br
Reactant: NCCN
Product: CCc1ccc(OC)c(CC)c1CC1=NCCN1

Procedure:
2-(2,6-Diethyl-3-methoxy-benzyl)-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-1,3-diethyl-4-methoxy-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 247.4 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
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: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O (7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh3)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl (3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4]
Reactant: COC(=O)c1sccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCCCC#Cc1ccsc1C(=O)OC

Procedure:
This product was prepared from 3-(toluene-4-sulfonyloxy)-thiophene-2-carboxylic acid methyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (71 mg, 60%); 1H NMR δ (CDCl3): 7.32 (d, J=5.03 Hz, 1H), 7.01 (d, J=5.10 Hz, 1H), 3.81 (s, 3H), 2.42 (t, J=7.25 Hz, 2H), 1.57 (p, J=7.19 Hz, 2H), 1.45-1.26 (m, 4H), 0.87 (t, J=7.2 Hz, 3H); LCMS m/z: 236.
Reaction SMILES: C([O:8][C:9](=[O:62])[C@:10]([CH3:61])([CH2:53][O:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][O:56]1)[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[N:30]=[N:31][N:32](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:33]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.CCOC(C)=O>[Pd]>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:26][C:27]([C:29]2[N:30]=[N:31][NH:32][CH:33]=2)=[O:28])[CH2:11][C@@:10]([CH3:61])([CH2:53][O:54][CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][O:56]2)[C:9]([OH:62])=[O:8])=[CH:15][CH:16]=1
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Yield: 156.2 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1-trityl-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid benzyl ester (7.5 g, 9.1 mmol) was combined with EtOAc (80 mL, 800 mmol). The resulting clear solution was purged with nitrogen and 10% Pd/C (0.05:0.45, Palladium:carbon black, 1.0 g, 0.94 mmol) was added. The resulting mixture was purged with hydrogen and then hydrogenated overnight at room temperature. The mixture was purged with nitrogen, the solids were filtered off, and the solvent was removed by rotary evaporation to yield the title compound (7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:44]([F:49])([F:48])C([O-])=O.[Na+].O>COCCOCCOC>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[C:44]([F:49])[F:48]
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOCCOC
Product: FC(F)=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 16 %

Procedure:
A mixture of 1.21 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.87 g of triphenylphosphine and 10 ml of diglyme was stirred at 160° C., to which a solution (5 ml) of 0.69 g of sodium chlorodifluoroacetate in diglyme heated to 60° C. was added dropwise. After stirring at 160° C. for 1.5 hours, the reaction mixture was returned to room temperature, poured into water and extracted twice with 50 ml of diethyl ether. The diethyl ether layers Were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.21 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-difluoro-2-propenyloxy)butyloxy)benzene (yield, 16%), nD23.0 1.5219.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)cc1

Procedure:
2,3,4-Trifluorobenzoic acid and methyl 4-aminobenzoate were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B, to afford after workup, crude 3,4-difluoro-2-[[4-(methoxycarbonyl)-phenyl]amino]benzoic acid as a cream solid. This material was then coupled directly with 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, and purified on flash silica (10% EtOAc as eluant) to give methyl 4-[[2,3-difluoro-6-[[(2-hydoxyethoxy)amino]carbonyl]phenyl]amino]benzoate (48%) as a white solid; m.p. (EtOAc/hexanes) 158-160° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.64 (br s, 1 H), 8.76 (br s, 1 H), 7.78 (d, J=8.8 Hz, 2 H), 7.41-7.27 (m, 2 H), 6.80 (dd, J=8.8, 1.8 Hz, 2 H), 4.67 (br s, 1 H), 3.78 (s, 3 H), 3.76 (t, J=4.8 Hz, 2 H), 3.50 (t, J=4.6 Hz, 2 H). Anal. Calcd for C17H16F2N2O5: C, 55.7; H, 4.4; N, 7.7. Found: C, 55.7; H, 4.4; N, 7.6. Step B: Preparation of 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]-phenyl]amino]benzoic acid
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3O)[C:6]=2[N:7]=1.O.CC#N.[C:25](OC(C)(C)C(Br)=O)(=[O:27])C.C([O-])(O)=O.[Na+]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([O:27][CH3:25])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]4[O:15][C@@H:12]34)[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(=O)OC(C)(C)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(N)nc2c1ccn2[C@@H]1O[C@H](CO)[C@H]2O[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 115 %

Procedure:
To a mixture of 2-amino-7-(β-D-ribofuranosyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.8 g, 6.0 mmol) in acetonitrile (80 mL) were added a solution of H2O/CH3CN (1:9, 1.08 mL) and then α-acetoxyisobutyryl bromide (3.5 mL, 24 mmol). After 2 h stirring at room temperature, saturated aqueous NaHCO3 (170 mL) was added and the mixture was extracted with EtOAc (300+200 mL). The combined organic phase was washed with brine (100 mL), dried (Na2SO4) and evaporated to a pale yellow foamy residue. This was suspended in anhydrous MeOH (80 mL) and stirred overnight with 25 mL of DOWEX OH− resin (previously washed with anhydrous MeOH). The resin was filtered, washed thoroughly with MeOH and the combined filtrate evaporated to give a pale yellow foam (1.92 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:42])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=1)[CH2:16][CH2:15][CH2:14]2)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:42])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=1)[CH2:16][CH2:15][CH2:14]2)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1)NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(CC(=O)N2CCCc3cc(CC(NC(C)=O)C(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
A solution of methyl (S) 2-acetylamino-3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [220 mg, Reference Example 4(1)] in dioxane (3 ml) was treated with a solution of lithium hydroxide hydrate (50 mg) in water (1 ml). The mixture was stirred at room temperature for 3 hours, then treated with water (5 ml), then acidified to pH 1-2 by the addition of dilute hydrochloric acid (with ice cooling). The resulting precipitate was extracted three times with ethyl acetate and the combined extracts were washed with water, then with brine, then dried and then evaporated. The residue was recrystallised from ethyl acetate to give the title compound (21 mg)as a white powder. LC-MS: RT=2.77 minutes (100% total area by ELS); MS (ES+) 581 (MNa+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([C:14]#[N:15])=[CH:4][N:3]=1.[CH:16]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([CH3:18])[CH3:17].Cl>CC(O)CC>[C:14]([C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([S:24](=[O:26])(=[O:25])[NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH:16]([CH3:17])[CH3:18])=[CH:28][CH:29]=2)=[N:3][CH:4]=1)#[N:15]
Reactant: CC(C)NCCCNS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cnc(Cl)nc1N1CCOCC1
Agent: Cl
Solvent: CCC(C)O
Product: CC(C)NCCCNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(N3CCOCC3)n2)cc1
Yield: 18.8 %

Procedure:
2-Chloro-5-cyano-4-morpholinopyrimidine (Method 55; 425 mg, 1.90 mmol), 4-[N-(3-isopropylaminopropyl)sulphamoyl]aniline (Method 1; 514 mg, 1.90 mmol) and 1M ethereal hydrogen chloride (189□l, 3.79 mmol) in 2-butanol (2 ml) was heated at 95° C. for 15 hours. The mixture was allowed to cool, silica was added and the volatiles were evaporated. The residue was purified by chromatography eluting with DCM/methanolic ammonia (100:0) increasing in polarity to (92:8) and the product was recrystallized from methanol to give the title compound (164 mg, 19%). NMR: 0.89 (d, 6H), 1.44 (m, 2H), 2.40 (t, 2H), 2.56 (m, 1H), 2.76 (t, 2H), 3.68-3.74 (m, 4H), 3.83-3.90 (m, 4H), 7.69 (d, 2H), 7.83 (d, 2), 8.49 (s, 1H), m/z: 460.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]([O:17]C)=[CH:5][CH:4]=1.[N+]([O-])(O)=O>O1CCOCC1.[Ag]=O>[CH3:13][C:11]1([CH3:14])[CH2:10][CH2:9][C:8]([CH3:15])([CH3:16])[C:7]2[C:6](=[O:17])[CH:5]=[CH:4][C:3](=[O:2])[C:12]1=2
Reactant: COc1ccc(OC)c2c1C(C)(C)CCC2(C)C
Agent: O=[Ag]
Solvent: O=[N+]([O-])O
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)C2=C1C(=O)C=CC2=O

Procedure:
To a solution of 17.42 g (0.07 mole) of 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene, obtained in Example VIa, in 340 cm3 of dioxane, cooled to +5° C., there are added, with stirring, 34.7 g (0.28 mole) of silver oxide, AgO(II), then rapidly drop-by-drop, 70 cm3 (0.42 mole) of 6N HNO3.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[CH2:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:12]>C1(C)C=CC=CC=1.O>[CH2:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][C:30]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCCCCCCO
Reactant: CC[C@H]1CC[C@H](CCc2ccc(-c3ccc(Cl)nn3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@H]3CC[C@H](CC)CC3)cc2)nn1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
A solution of n-heptanol (3.5 g) in toluene (50 ml) was dropwise added to a suspension of sodium hydride (about 55%) (1.5 g) in toluene (50 ml). The mixture was agitated for 30 minutes, dropwise adding a solution of 3-(4-(2-(trans-4-ethylcyclohexyl)ethyl)phenyl)-6-chloropyridazine (5 g) obtained above, in toluene (100 ml), heating the mixture under reflux for 3 hours. The reaction solution was poured in water. The resulting organic layer was washed with water until the organic layer became neutral. After drying it over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure and recrystallizing the residue from ethanol, the captioned 3-(4-(2-(trans-4-ethylcyclohexyl)ethyl)phenyl)-6-heptyloxypyridazine (3.7 g) was obtained. ##STR12##
Reaction SMILES: [CH:1]([C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)=O.[O:21]=[C:22]([CH2:43][C:44]#[C:45][CH2:46][CH3:47])[CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:12]([O:11][C@@H:10]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][C:6](=[O:20])[O:7]2)[C@H:3]1/[CH:1]=[CH:23]/[C:22](=[O:21])[CH2:43][C:44]#[C:45][CH2:46][CH3:47])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC#CCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCC#CCC(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Yield: 98.1 %

Procedure:
A solution of 7.4 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (E. J. Corey et al., J. Chem. Soc., 91, 5675 (1969)) and 10.3 g of the phosphorane prepared in Example (23b) in 200 ml of absolute toluene is stirred at room temperature for 5.5 hours. The reaction solution is concentrated in vacuo and the residue is chromatographed over silica gel by gradient elution in hexane/40% ethyl acetate. 9.7 g of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[C:8]([N:13]=[N+]=[N-])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]2[C:6]([CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[NH:13]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(=Cc1ccc(OC)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(OC)cc2[nH]1

Procedure:
Toluene (185 ml) is added to methyl 4-methoxy-α-azidocinnamate (PREPARATION 61, 7.73 g) and the reaction is brought to reflux and maintained at reflux for 3 hr. Then the reaction is concentrated under reduced pressure and triturated with hexane. The solids are filtered and dried under reduced pressure to give the title indole, HRMS Calcd. for C11H11NO3 : 205.0739, found: 205.0736; NMR (300 MHz, CDCl3) 8.75, 7.47, 7.11, 6.76-6.73, 3.86, 3.79 δ.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].Cl>C(O)C>[OH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: COCOc1cnccc1CCCO
Agent: Cl
Solvent: CCO
Product: OCCCc1ccncc1O
Yield: 73 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (3.67 g, 18.6 mmol) obtained in Example 2 is dissolved in ethanol (100 ml), and thereto is added a 15% aqueous hydrochloric acid solution (20 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate), and further recrystallized from diethyl ether to give the title compound (2.08 g) as colorless crystals, m.p. 123-126° C.