Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][C:16]([CH2:24][O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:20](OC)=[O:21])[CH2:15]3)[O:12][C:11]2=[O:33])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[BH4-].[Li+]>C1COCC1>[OH:21][CH2:20][C:16]1([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:17][CH2:18][CH2:19][C:13]2([O:12][C:11](=[O:33])[N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:14]2)[CH2:15]1
Reactant: COC(=O)C1(COCc2ccccc2)CCCC2(CN(Cc3ccc(OC)cc3)C(=O)O2)C1
Agent: [Al+3]
Agent: [BH4-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3(CCCC(CO)(COCc4ccccc4)C3)OC2=O)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
To a solution of methyl 3-{[4-(methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (6.523 g, 14.38 mmol) in THF (27.9 mL) under nitrogen at −78° C. was added lithium aluminium hydride (1M in THF, 71.9 mL, 71.9 mmol) over 10 minutes and stirred for 2 days. The reaction was then quenched slowly with water (5 mL), followed by the addition of 2N HCl (200 mL). The reaction mixture was then extracted with EtOAc (2×150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. To the solution in THF (27.9 mL) was added lithium borohydride (2N in THF, 10.79 mL, 21.57 mmol) and the mixture was stirred for 30 minutes, then heated at 50° C. The additional lithium borohydride (2N in THF, 3.6 mL, 7.19 mmol) was added. The reaction mixture was then cooled to RT and quenched slowly with 2N HCl (100 mL). The mixture was then extracted with EtOAc (2×100 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The mixture was then loaded onto florisil and purified using silica gel chromatography CISCO): 10-80% ethyl acetate/hexanes (30 min), 80% (5 min), 80 g silica. The product eluted at 26 minutes to yield 7-(Hydroxymethyl)-3-{[4-(methyloxy)phenyl]methyl}-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]decan-2-one as a colorless oil (5.2 g, 81% yield). MS (m/z) 426.1 (M+H+).
Reaction SMILES: OO.[CH2:3]([N:5]([CH2:23][CH3:24])[CH2:6][CH2:7][NH:8][C:9]1[N:10]=[N+:11]([O-:22])[C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][C:13]=2[N:14]=1)[CH3:4].C(O)(C(F)(F)F)=[O:26]>C(Cl)Cl.N>[CH2:23]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][NH:8][C:9]1[N:10]=[N+:11]([O-:22])[C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][C:13]=2[N+:14]=1[O-:26])[CH3:24]
Reactant: CCN(CC)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CCN(CC)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
H2O2 (70%, 0.37 mL, ca. 7.3 mmol) was added dropwise to a stirred solution of TFM (1.0 mL, 7.3 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 8 (219 mg, 0.7 mmol) and TFA (280 μL, 3.6 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 9 (91 mg, 31%) as a red solid: mp (MeOH) 138-141° C.; 1H NMR δ 8.11 (d, J=8.7 Hz, 1H, H-5), 7.70 (d, J=8.7 Hz, 1H, H-6), 7.44 (br s, 1H, NH), 3.70 (br t, J=7.4 Hz, 2H, H-9), 3.58-3.63 (m, 2H, CH2N), 3.03 (br t, J=7.7 Hz, 2H, H-7), 2.77 (br dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.63 (q, J=7.1 Hz, 4H, 2×CH2N), 2.22 (br p, J=7.7 Hz, 2H, H-8), 1.08 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 149.0, 144.7, 138.6, 138.3, 132.7, 129.0, 115.7, 51.2, 46.8 (2), 38.8, 35.1, 32.9, 25.6, 11.7 (2). Anal. calcd for C16H23N5O2.½H2O: C, 58.9; H, 7.4; N, 21.5. Found: C, 59.2; H, 7.2; N, 21.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]2[C:32](=[O:33])[O:31]C(C)(C)[O:29][C:28]2=[O:36])=[O:22])=[CH:16][CH:15]=1.O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:23][CH2:24][CH2:25][CH2:26][CH:27]([C:32]([OH:33])=[O:31])[C:28]([OH:36])=[O:29])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCCC3C(=O)OC(C)(C)OC3=O)cc2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCCC(C(=O)O)C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propyl)urea (100 mg, 0.19 mmol, 1.00 equiv) in 2,2,2-trifluoroacetic acid (10 mL), and water (2 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with methanol:water (60%). The residue was lyophilized. This resulted in 36.3 mg (30%) of a TFA salt of the title compound as a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 8.55 (s, 1H), 7.64 (s, 1H), 7.39-7.42 (d, J=8.7 Hz, 2H), 7.09-7.12 (d, J=8.4 Hz, 2H), 6.79 (s, 1H), 6.23-6.27 (m, 1H), 4.33-4.50 (m, 3H), 3.62 (s, 1H), 3.19 (m, 1H), 3.08-3.10 (d, J=5.7 Hz, 2H), 2.94 (s, 3H), 1.70-1.77 (d, J=23.1 Hz, 2H), 1.41-1.46 (d, J=12 Hz, 2H). MS (ES, m/z): 494 [M+H]+.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18](=[O:21])[CH2:19]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH:26]1[CH:30]=[N:29][N:28]=[N:27]1.C(N(CC)CC)C>C(#N)C>[NH:26]1[C:30]([CH2:19][C:18]([C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:21])=[N:29][N:28]=[N:27]1
Reactant: c1nnn[nH]1
Reactant: CCCCCCCCCCCCCCOc1ccccc1C(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccccc1C(=O)Cc1nnn[nH]1

Procedure:
To a solution of 14.6 g of o-tetradecyloxyphenacylbromide in 75 ml of acetonitrile was added a solution of 2.8 g of tetrazole and 4.0 g of triethylamine in 75 ml of acetonitrile. The reaction mixture was stirred at reflux temperature for 2 hours then evaporated to dryness. The residue was dissolved in chloroform and the organic layer washed with water, dried over magnesiumsulfate, filtered and evaporated to give the crude compound. Recrystallisation from petrol (b.p. 60°-80° C.) gave the acetophenone derivative as a fine white powder. Yield: 12.7 g; m.p. 67° to 69° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(C1C=CC(OC)=CC=1)#C.BrC1C(N)=NC=C(Br)N=1.[H-].[Na+].[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C#Cc2nc(Br)cnc2N)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: C#Cc1ccc(OC)cc1
Agent: Nc1ncc(Br)nc1Br
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3nc(Br)cnc3n2COCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a round bottom flask was added 5-bromo-3-((4-methoxyphenyl)ethynyl)pyrazin-2-amine (11.9 g, 39.1 mmol, prepared using A from 1-ethynyl-4-methoxybenzene with 3,5-dibromopyrazin-2-amine), DMF (98 mL) and NaH (60% in mineral oil) (2.03 g, 50.8 mmol). The reaction mixture was stirred at room temperature for about 2 h and then 2-(trimethylsilyl)ethoxymethyl chloride (7.63 mL, 43.0 mmol) was added. The reaction mixture was stirred at rt for about 2 h. To the reaction mixture was added NaH (60% in mineral oil) (0.469 g, 19.55 mmol). The reaction mixture was stirred for about 24 h at rt. The reaction mixture was quenched with water (400 mL) and extracted with EtOAc (3×250 mL). The organic layer was washed with brine (250 mL), dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (300 g Silicycle® column, DCM/MeOH 1:0 to 10:1) to give the title compound (14.3 g; 84%): LC/MS (Table 2, Method b) Rt=3.11 min; MS m/z 436.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:28]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH2:26][C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:28])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Reactant: COc1ccc(C(=O)CBr)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)c(F)c21

Procedure:
1-Ethyl-6,8-difluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from 1-ethyl-6,8-difluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid (0.50 g, 1.48 mmole) and 2-bromo-4′-methoxy-acetophenone (0.43 g, 1.86 mmole) by a method similar to that described for Example 4 (63% yield). Mp: 190° C. (dec). 1H NMR (DMSO-d6) δ 1.44 (t, 3H, J=7.0), 2.69 and 3.24 (two m, 8H), 3.84 (s, 3H), 3.87 (s, 2H), 4.58 (q, 2H, J=7.0), 7.05 (m, 2H), 7.85 (d, 1H), J=12.0), 8.01 (m, 2H), 8.92 (s, 1H), 14.92 (br s, 1H). Anal. Calcd. for C25H25F2N3O5•0.25 H2O: C, 61.28; H, 5.25; N, 8.58. Found: C, 61.25; H, 5.23; N, 8.67.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Mg]Br.CO[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=1>O1CCCC1>[F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: FC(F)(F)CCCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCCCCC(F)(F)F)=N1

Procedure:
Following the procedures of Example 1(a), (b) and (c), 12,12,12-trifluorododecylmagnesium bromide (from 29.19 mmoles of 12,12,12-trifluorododecyl bromide and 25.71 mmoles of magnesium) was reacted with 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (20.17 mmoles) in tetrahydrofuran to give 2-[2-(12,12,12-trifluorododecyl)phenyl]-4,4-dimethyloxazoline. The oxazoline (14.39 mmoles) was converted to the methiodide salt and then reduced with sodium borohydride (13.43 mmoles) to yield the desired product as an oil.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][C:18](=[O:22])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][C@H:18]([OH:22])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,25R)spirostan-3-ol-11-one (Aldrich Chemical Company, Milwaukee, Wis. or Steraloids Inc., Wilton, N.H., or see preparation G13) was converted into the title compound via reduction with lithium aluminum hydride in THF at room temperature according to the procedure described in J. Am. Chem. Soc., 1951, 73, 1777.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]cnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-benzo[d]imidazole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=8.1, 4.8, 1.0 Hz, 1H), 7.75-7.98 (m, 1H), 7.99-8.17 (m, 1H), 8.34-8.56 (m, 3H), 8.82 (dd, J=5.1, 1.7 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10]C(C)(C)C)=O)#[N:2].C(O)(C(F)(F)F)=O.[CH2:22]([C:33]1[CH:41]=[CH:40][C:36](C(O)=O)=[CH:35][CH:34]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCOC(C)=O>[CH2:22]([C:33]1[CH:34]=[CH:35][C:36]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:1]#[N:2])=[O:10])=[CH:40][CH:41]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C#N
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCc1ccc(C(=O)N2CCC[C@H]2C#N)cc1
Yield: 40.9 %

Procedure:
General procedure D was used to deprotect 0.447 grams (2.3 mmols) of 28. After standard work-up procedures, general procedure E was used to couple 2.3 mmols of the TFA salt of 28 to 0.635 grams (2.3 mmols) of 4-undecylbenzoic acid at 50° C. After work-up, 0.334 grams (0.94 mmols, 41%) of the title product was isolated as a yellow solid by flash chromatography (25% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3) δ 7.24 (dd, J=12.2, 4.4 Hz, 2H), 7.04 (t, J=7.7 Hz, 2H), 4.97 (s, 1H), 3.88 (s, 1H), 3.31 (dt, J=18.1, 9.0 Hz, 1H), 2.77-2.64 (m, 1H), 2.63-2.54 (m, 1H), 2.24-2.12 (m, 1H), 1.60 (dt, J=15.1, 7.3 Hz, 4H), 1.29 (d, J=10.9 Hz, 14H), 0.88 (t, J=6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.97, 146.29, 128.42, 128.18, 127.63, 127.17, 118.73, 49.51, 46.85, 46.20, 35.84, 31.91, 31.20, 30.27, 29.64, 29.61, 29.56, 29.46, 29.33, 29.23, 25.57, 22.68, 14.12.
Reaction SMILES: NN=C([C:10]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3N(N)[C:14]=2[CH:13]=[CH:12][C:11]=1[CH2:26][C:27]1C=CC=CC=1)C1C=CC=CC=1.[ClH:33].N1CCC(=O)CC1.S(=O)(=O)(O)O.[NH3:46]>O.C(O)C>[ClH:33].[CH:27]1[N:46]2[C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[CH:18]=[CH:19][C:20]3=[C:10]2[C:11](=[CH:12][CH:13]=[CH:14]3)[CH:26]=1
Reactant: NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N
Reactant: N
Agent: Cl
Agent: O=C1CCNCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: C1=Cc2cccc3ccn(c23)-c2ccccc21
Reaction time: 0.67 h

Procedure:
A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino-10,11-dihydro-5H-dibenz[b,f]azepine) and 14.8 g of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for 15 minutes 1,2,3,4,4cooled; 8,9,14a-octahydropyridoof 20 g. indoloconcentrated sulfuric acid in 250 ml. ethanol was added. The resulting mixture was reheated on the steam bath for an additional 40 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1 liter of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined ethereal extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and C (dec). 1N hydrochloric acid, and dried in vacuo at 100° to yield 1,2,3,8,9-hexahydropyrido[4',3':2,3]=indolo[1,7ab][1]benzazepine hydrochloride, m.p. 309°, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallizing it from benzene regenerated the free 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine, m.p. 134°-136° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccnn1
Reactant: NCCCN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1cccnn1

Procedure:
Reacting 3-chloropyridazine with 1,3-diaminopropane in ethanol containing sodium ethoxide according to the procedure of Example 89 gives 3-(3-aminopropylamino)pyridazine. Using this intermediate as the starting material in the procedure of Example 18 gives N-cyano-N'[3-(3-pyridazinylamino)propyl]guanidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].C[Si](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.[Ag-]=O.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:8]1[CH:7]=[N:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)c1ccccn1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd+]
Agent: O=[Ag-]
Agent: C=C[CH2-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccn2)cn1
Temperature: 90 °C
Yield: 48 %

Procedure:
This compound is synthesized as described by adaptation of the following reference: Tye et al., Tet. Lett., 2008, 49, 3939. To a stirred suspension of methyl-5-bromo-2-pyridine carboxylate (0.25 g, 1.16 mmol) and 2-(trimethylsilyl)pyridine (0.48 mL), 3.48 mmol) in anhydrous N,N-dimethyl formamide (7.5 mL) is added silver (I) oxide (0.27 g, 1.16 mmol), allyl palladium chloride dimer (21 mg, 5 mol %) and tetrabutyl ammonium fluoride (1M in THF, 0.116 mL). The reaction is heated at 90° C. for 18 h. The reaction mixture is filtered and washed with EtOAc. The filtrate is concentrated under reduced pressure. Purification by column chromatography (silica, eluent DCM, 0-2% MeOH) gives 0.12 g (48%) of methyl 2,3′-bipyridine-6′-carboxylate. m/z=215 [M++H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:11][CH:12]=2)[CH:7]=1.C1COCC1.[OH-].[Na+:27]>CO>[Na+:27].[Na+:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])[O:11][CH:12]=2)[CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])[O:11][CH:12]=2)[CH:7]=1
Reactant: O=C(O)CCCCc1nc(-c2cc(Cl)ccc2O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])CCCCc1nc(-c2cc(Cl)ccc2O)co1

Procedure:
Combine 5-[4-(5-Chloro-2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid (2.71 g, 9.2 mmol) with THF (10 mL), MeOH (10 mL) and 1N NaOH (18.4 mL) and stir at RT for 2 h. Concentrate the mixture and dry the residue overnight in vacuo at 40-50° C. to allow for recovery of 5-[4-(5-Chloro-2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid disodium salt (3.0 g, 96%). MS (ES): (M+1)+ 296.1, 298.1 m/z.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:21])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:11][C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(OCC)(=O)C.O>[Cl-].[Na+].O>[C:1]([NH:5][C:6](=[O:21])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:11][C:10]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)NC(C)(C)C
Temperature: 100 °C
Yield: 93.8 %

Procedure:
A mixture of 6.0 g (19 mMol) of N-tert.-butyl-6-chloro-4-o-tolyl-nicotinamide and 12 ml (138 mMol) morpholine was heated at 100° C. for 4 hours. After cooling to room temperature, extractive work-up with ethyl acetate, water and brine yielded 6.3 g (91%) of N-tert.-butyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide as a brown crystalline foam.
Reaction SMILES: C(NCC)C.CC(O)(C)C.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:14].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][CH2:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)=[O:31])=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCNCC
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: O=C(CCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a solution of zinc(II) chloride (19.62 g, 144 mmol) in benzene (108 mL) were added diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and the mixture was stirred at room temperature for 2 hours. 2-Bromo-1-(4-bromophenyl)ethanone (20.0 g, (72 mmol) and 1-(4-bromophenyl)ethanone (21.48 g, 108 mmol) were added in one portion, and the mixture was stirred overnight (18 hours). The reaction mixture was quenched with 5% H2SO4 (500 mL) and stirred vigorously to induce precipitation of the product, which was collected by vacuum filtration and washed with benzene, water, methanol, and then dichloromethane, successively. The product was dried under vacuum to give the title compound as a white solid (11.15 g, 39.1% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[C:25]=2[CH3:33])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:34].[Li+]>C(COC)OC.O.[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[C:25]=1[CH3:33])[C:20]([OH:22])=[O:34])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(C)c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reaction time: 2.5 h

Procedure:
A solution of 1.001 g (2.2 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 35.8 ml of dimethoxyethane and 18 ml of water is treated, at RT, with 8.8 ml of a 1M solution of lithium hydroxide in water, and this reaction mixture is stirred for 2.5 h. It is then transferred to a separating funnel and diluted with 108.5 ml of sat. ammonium chloride solution and 9 ml of a 10% citric acid solution (both being cold); the whole is then extracted with ethyl acetate and a little THF. The title compound, which is subjected to further processing without being purified, is obtained after washing the organic phase with (cold) saline and drying it over sodium sulfate. TLC Rf (hexane:ethyl acetate 1:1)=at the start. FAB-MS (M+H)+ =472; IR(KBr) inter alia: 1724, 1666, 1527 and 1169 cm-1. 1H-NMR(CD3OD) inter alia: 7.31-7.11 (m, 5H); 6.93 and 6.68 (each d, each 1H); 3.76 (s, 3H); 3.23 and 2.59 (each d×d, each 1H); 2.21 and 2.12 (each s, each 3H); 1.27 (s, 9H).