Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@:3]1([OH:25])[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)#[CH:2].[Br:26]Br>CO.Br.C(Cl)Cl>[Br:26][CH2:14][C:13](=[O:15])[C@@H:12]1[C@:16]2([CH3:24])[C@H:9]([C@H:8]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C@@H:5]([CH2:4][C@:3]([C:1]#[CH:2])([OH:25])[CH2:22][CH2:21]2)[CH2:6][CH2:7]3)[CH2:10][CH2:11]1
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: BrBr
Agent: Br
Solvent: ClCCl
Solvent: CO
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A solution of 3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (3 g, 8.77 mmol) in MeOH (110 mL) was treated with two drops of HBr (48%), followed by bromine (0.5 mL, 10.8 mmol). The mixture was stirred at room temperature for 1 hr and was poured into ice-water. The separated solid was collected by filtration, washed with water, and dried (3.2 g). This semi-dried solid was then dissolved in EtOAc and dried over anhyd. MgSO4. Filtration and removal of the solvent gave the crude bromo derivative. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:EtOAc mixture (4:1) gave 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (3.2 g).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:24](O)[CH3:25]>>[C:5]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH2:24][CH3:25])=[O:18])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)Nc1ccccc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCCCCCCC(=O)Nc1ccccc1C(=O)OCC
Reaction time: 2 h
Yield: 89.2 %

Procedure:
Thionyl chloride was dropped to ethanol and the mixture was stirred for 2 hours. Then, N-n-octanoylanthranilic acid was added to the mixture and reaction was allowed to proceed for 3 days at the room temperature. After the reaction, the solvent was removed and ethyl N-n-octanoylanthranilate was obtained from the remaining reactant after the purification by column chromatography with the yield of 89.2%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([N+:14]([O-])=[O:15])([CH3:13])[CH3:12].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[N+:14]([C:11]([CH3:13])([CH3:12])[CH3:10])[O-:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1cccc(F)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1cccc(F)c1

Procedure:
To a suspension of 3-fluorobenzaldehyde (327.5 mg, 2.64 mmol), 1,1-dimethylnitroethane (542.3 mg, 5.26 mmol) and zinc (517.9 mg, 7.92 mmol) in ethanol (3.0 ml) was added acetic acid (946.2 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH:4]([C:7]([N:17]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:18]([C@H:20]([NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](=[O:10])[NH2:9])([CH3:6])[CH3:5].C(O)(=O)C>C(OCC)C.O1CCCC1>[CH3:3][O:24][C:23](=[O:25])[CH2:22][CH2:21][C@H:20]([C:18](=[O:19])[N:17]([C:7]([CH:4]([CH3:6])[CH3:5])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:8](=[O:10])[NH2:9])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:26][C:27]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:28]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N(C(=O)[C@@H](CCC(=O)O)NC(=O)Nc1ccccc1)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](NC(=O)Nc1ccccc1)C(=O)N(c1ccccc1)C(C(N)=O)(c1ccccc1)C(C)C

Procedure:
A solution of diazomethane in diethyl ether (generated from N-methylnitroso urea, 623 mg and 40% aqueous potassium hydroxide, 2 mL) was added dropwise to a solution of Example 4 (11.2 mg, 0.0217 mmol) in tetrahydrofuran (2 mL) until a yellow color persisted. Acetic acid was added until yellow color disappeared and the solvents were removed in vacuo. RP-HPLC (45% to 64%, 30 min) gave the titled product (10.3 mg) as a white lyophile. (45% to 64%, 30 min) Tr =13.07 min. 1H NMR (300 MHz, CDCl3) d 1.0 (2×d, J=7.0 Hz, 6H), 1.90 (m, 1H), 2.07 (m, 1H), 2.20 (m, 1H), 2.41 (m, 1H), 3.40 (d, J=16.6 Hz, 1H), 4.21 (s, 3H), 4.36 (d, J=16.6.0 Hz, 1H), 4.70 (m, 1H), 5.20 (sept, J=6.0 Hz, 1H), 6.57 (d, J=7.0 Hz, 1H), 6.88 (m, 4H), 7.10 (m, 4H), 7.21 (br, 2H), 7.38 (m, 4H), 7.59 (d, J=7.0 Hz, 2H), 8.30 (s, 1H). C31H36N4O6 requires m/z 560.6502; found 560.6541.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].B1(CC2C=CC=CC=2)C2CCCC1CCC2.C1(P(C2CCCCC2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[C:43](OC)=[CH:42][CH:41]=[CH:40][C:39]=2OC)CCCCC1.BrC1C=CC=C2[C:56]=1[C:57]([CH2:69][N:70]([CH:78]1[CH2:80][CH2:79]1)[C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:58][N:59]2[CH2:64][CH2:65][CH2:66][O:67][CH3:68]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH2:33]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]2[C:56]=1[C:57]([CH2:69][N:70]([CH:78]1[CH2:79][CH2:80]1)[C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:58][N:59]2[CH2:64][CH2:65][CH2:66][O:67][CH3:68])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Br)cccc21
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(CB2C3CCCC2CCC3)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Cc3ccccc3)cccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 499.2 %

Procedure:
Potassium phosphate (498 mg), a 0.5M tetrahydrofuran-solution of B-benzyl-9-BBN (2.8 ml), palladium acetate(II) (21 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (38.5 mg) were added to a solution of tert-butyl {[4-bromo-1-(3-methoxypropyl)-1H-indol-3-yl]methyl}cyclopropylcarbamate (205 mg) in N,N-dimethylformamide (4.3 ml) and the mixture was stirred under argon atmosphere at 80° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=20/1 to 2/1) to give tert-butyl {[4-benzyl-1-(3-methoxypropyl)-1H-indol-3-yl]methyl}cyclopropylcarbamate (210 mg) as a yellow oil.
Reaction SMILES: O[C@@:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[N-:39]=[N+:40]=[N-:41].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:39]([C:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2)=[N+:40]=[N-:41]
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@]2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CCCC2(N=[N+]=[N-])c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (S)-methyl 5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (100 mg, 0.185 mmol) and sodium azide (36.1 mg, 0.555 mmol) in DCM (2 mL) at rt was added TFA (0.016 mL, 0.203 mmol) dropwise and the mixture was stirred at rt for 16 h, after which time the reaction was heated to 40° C. for 5 days. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude methyl 5-azido-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a brown oil, which was used as such for the following transformation. MS ESI calcd for C27H22F3N7O2S [M+H]+ 566, found 566.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].C[OH:25]>>[OH:25][CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: C=CC(NC(=O)OC(C)(C)C)C1CCC2(CC1)OCCO2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC(CCO)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 250 mL round bottom flask was charge with tert-butyl (1-(1,4-dioxaspiro[4.5]decan-8-yl)allyl)carbamate (5.8 g, 18.6 mmol) and methanol (207 mL). The mixture was cooled to −78° C. and ozone was bubble through the solution at a rate of 3 L/min for 1 hour. The mixture turned pale blue in color after 30 minutes. After 1 hour air was bubble through the solution for 30 minutes until the blue color disappeared. Sodium borohydride (2.82 g, 74.5 mmol) was added to the mixture in 4 portions. The mixture was gradually warmed to room temperature. After 6 h at room temperature the mixture quenched with saturated aqueous ammonium chloride. Dilute with water and extract with ethyl acetate. Dry organic layer with MgSO4, filter, and concentrate in vacuo to give tert-butyl (3-hydroxy-1-(1,4-dioxaspiro[4.5]decan-8-yl)propyl)carbamate (5.1 g, 16.2 mmol) as a clear oil.
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:37]([O:39]C)=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-].C1(NC2CCCCC2)CCCCC1.CCOCC>C1COCC1.CO>[NH:1]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:37]([OH:39])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 63.7 %

Procedure:
compound NR66. Saponification of N-Boc-Tyr(Bn)-Ala-Trp-OMe (580 mg, 0.902 mmol) in THF (5 mL) by 1 M aqueous LiOH (2 mL, 2 mmol) at 4° C. for 1 hour, afforded after acidic treatment and precipitation of the residue with water crude N-Boc-Tyr(Bn)-Gly-Trp-OH. The crude product in MeOH (0.5 mL) was treated by dicyclohexylamine (0.18 mL, 0.91 mmol) and then ether (10 mL). After filtration, the resulting solid was dissolved in CH2Cl2 (10 mL) and washed by 10% aqueous citric acid. The organic phase was dried over MgSO4 and concentrated to afford N-Boc-Tyr(Bn)-Ala-Trp-OH (361 mg, 64%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, J=7 Hz, 3H, CH3), 1.28 (s, 9H, (CH3)3), 2.62 and 2.86 (ABX system, 2H, CH2β), 3.09 and 3.18 (ABX system, 2H, CH2β), 4.10 (m, 1H, CHα), 4.35 (m, 1H, CHα), 4.46 (m, 1H, CHα), 5.03 (s, 2H, CH2 (OBn)), 6.87-7.54 (m, 15H, 14 aromatic H+1 NH), 7.96 (d, J=7.5 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 10.84 (s, 1NH). 13C NMR (75 MHz, CDCl3) δ 18.2 (CH3), 27.2 (CH2 Trp), 28.3 ((CH3)3), 37.3 (CH2 Tyr), 48.9, 53.3, 55.7 (CHα Ala, Tyr or Trp), 70.0 (CH2 (OBn)), 80.7 (C(CH3)3), 109.5 (aromatic C), 111.5, 115.0, 118.6, 119.5, 121.9, 123.8, 127.5, 127.6, 128.1, 128.6, 130.4 (aromatic CH), 136.1, 137.0, 137.1 (aromatic C), 155.8, 157.8 (Car-O or CO carbamate), 171.9, 172.3, 174.2 (2 CO amide or CO acid). Anal. Calcd. for C35H40N4O7, 1.5H2O: C, 64.11%; H, 6.61%; N, 8.54%. Found: C, 64.19%; H, 6.36%; N, 8.79%.
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C:12]12[CH2:17][CH2:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2
Reactant: CCOC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C12CCC(N)(CC1)CC2
Yield: 100.4 %

Procedure:
Ethyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (40.0 g) was dissolved in ethanol (400 mL). To this solution, 10% palladium-carbon (4.00 g) was added and the mixture was stirred at room temperature for 6 hours in a stream of hydrogen. The catalyst in the reaction mixture was filtered through a Celite pad and the filtered catalyst, together with the Celite pad, was washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was dried under reduced pressure to give ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (23.9 g).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14].[C:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([C:21](=[N:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[OH:14])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CCC[C@H]1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of (1R,2R)-2-aminocyclopentanol TFA salt (630 mg, 2.93 mmol) was added diphenylmethanimine (490 uL, 2.93 mmol) and TEA (0.5 mL, 3.58 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure and purified by ISCO flash chromatography using EtOAc and hexane as eluting solvent to yield (1R,2R)-2-(diphenylmethyleneamino)cyclopentanol (697 mg, 90% yield) as a colorless gum. HPLC: RT=1.96 min [M+H] 266.13 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.49-1.64 (m, 2H), 1.66-1.91 (m, 3H), 2.08-2.24 (m, 1H), 3.55-3.71 (m, 1H), 4.31-4.47 (m, 1H), 7.15-7.25 (m, 2H), 7.29-7.53 (m, 6H), 7.61-7.67 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][CH:11]=O.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Clc1ccc2nccn2n1
Yield: 70.3 %

Procedure:
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 ml (40 mmol) of chloracetaldehyde (55% strength in water) in 15 ml of n-butanol at 120° C. for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70%) of the desired product were isolated in the form of an amorphous white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:39][CH2:40][Br:41])(=[O:38])[CH3:37]>C(#N)C>[Br-:41].[C:36]([O:39][CH2:40][N:33]1[CH2:34][NH+:30]([CH2:29][C@@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:35])[C@H:10]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[N:26][N:25]=[N:24]4)=[CH:19][CH:18]=3)[C:13]2=[O:28])[CH3:11])[N:31]=[CH:32]1)(=[O:38])[CH3:37]
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)OCBr
Solvent: CC#N
Product: CC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4cnnn4)cc3)C2=O)C1
Product: [Br-]
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.5 g) and acetonitrile (10 ml) was added bromomethyl acetate (0.2 ml), and the mixture was stirred for 16 hours at 50° C. The reaction mixture was purified by silica gel flush chromatography (silica gel: 25 g, eluent: ethyl acetate→acetone→acetone/ethanol=10/1). The residue purified was crystallized from ethanol to give 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium bromide (Compound 11, 0.39 g) as colorless crystals.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH3:4])#[N:2].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C>ClCCl.CN(C=O)C>[CH2:14]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([CH:3]([C:1]#[N:2])[CH3:4])[CH:6]=1)[CH3:15]
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cccc(C(C)C#N)c1
Reaction time: 1 h

Procedure:
To a solution of 700 mg 3-(1-Cyano-ethyl)-benzoic acid in 20 ml dichloromethane were added dropwise 610 mg oxalyl chloride and 2 drops of DMF at RT. After stirring for 1 hr, 10 ml ethanol were added and stirring was continued for another hr. The solvents were evaporated, the residue dissolved in dichloromethane and washed with aqueous sodium bicarbonate solution. The dichloromethane phase was dried, evaporated and the residue purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20].O>CN(C=O)C>[Cl:1][C:2]1[N:12]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:19](=[O:20])[C:18]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:17]=3[Cl:16])=[CH:28][CH:27]=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13]
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 16 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with ether to provide the title compound as yellowish brown powder (471 mg, yield 49%).
Reaction SMILES: [C:1]12([CH2:10][NH2:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[CH:12](=[C:10]([NH2:11])[C:1]12[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)C2CCC1(CN)CC2
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C2CCC1(C(N)=Cc1ccccc1)CC2

Procedure:
10-Bornanamine (824mg) in toluene (20ml) was treated with benzaldehyde (0.55ml) and the solution refluxed under nitrogen under a Dean and Stark water trap for four days. Evaporation of the solvent in vacuo afforded impure 10-benzylidene-10-bornanamine which was dissolved in dimethoxyethane (10ml) containing lithium aluminium hydride (112mg.). The resulting mixture was refluxed for 2.25 hours, cooled, and the excess hydride decomposed by the addition of water. The precipitated inorganic material was removed by filtration and the solvent was evaporated in vacuo. The residual gum was triturated with 2N-hydrochloric acid to afford an insoluble hydrochloride which was collected by filtration and then partitioned between ether and 2N-sodium hydroxide. The dried ethereal layer was evaporated in vacuo to give a yellow oil which was dissolved in ether and treated with ethanolic hydrogen chloride. The precipitated solid was collected and recrystallized from water to give title compound m.p. 310° (Found: C, 72.65; H, 9.65; Cl, 13.3; N, 4.95. C17H26ClN requires C, 72.95; H, 9.35; Cl, 12.65; N, 5.0%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([Li])CCC.CN(C)CCN(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([CH2:33]Br)[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]2[C:28](=[CH:29][CH:30]=1)[CH2:31][C:3]1([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[CH2:33]2
Reactant: O=C1Cc2ccccc2N1
Reactant: BrCc1ccc(Br)cc1CBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12Cc1ccc(Br)cc1C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL) was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) dropwise, followed by the dropwise addition of tetramethylethylenediamine (0.905 mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then a solution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533](1.87 g, 5.45 mmol) in THF (5 mL) was added dropwise. The reaction solution was stirred at −10 to −20° C. for 2 h and at ambient temperature for 16 h. The reaction mixture was partitioned between saturated NH4 CI (50 mL) and EtOAc (50 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2 SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc —100:0 to 50:50, to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: [Si]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])=[O:23])[CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C.CO.O.ClCCl>CO>[NH3:11].[CH2:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][C:22](=[O:23])[CH2:21][CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C@H:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=2)[CH3:35])[CH:15]=1)[CH3:34]
Reactant: CCOc1ccccc1CNC(=O)CCc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOc1ccccc1CNC(=O)CCc1cccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(CO)c2)c1
Product: N

Procedure:
Prepared from 3-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-ethoxybenzyl)propanamide (Preparation 47) according to the method for example 1 using methanol:water (2.4:1 v/v) instead of acetic acid as solvent and using dichloromethane:methanol: 880 ammonia (94:6:0.6 by volume) as the column eluent to give the title compound as a white solid.