Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[CH3:23][Mg]Br.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O.O>[OH:1][C:2]1([CH3:23])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(O)CN(C(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a cooled solution (ice water bath) of di-tert-butyl 6-oxo-1,4-diazepane-1,4-dicarboxylate (570 mg, 1.82 mmol) in THF (10 mL), was added dropwise a solution of methylmagnesium bromide (3 M in Et2O, 0.79 mL, 2.36 mmol). The mixture was allowed to warm to room temperature and stirred for 16 hr. Aqueous saturated ammonium chloride solution (5 mL) was added and the mixture diluted with EtOAc (30 mL) and water (30 mL). The layers were separated and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-70% EtOAc/isohexane) gave di-tert-butyl 6-hydroxy-6-methyl-1,4-diazepane-1,4-dicarboxylate as an oil (0.45 g). To a solution of this oil (0.45 g, 1.36 mmol) in MeOH (2 mL), was added HCl in 1,4-dioxane (4 M, 6.8 mL, 27.3 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure. The residue was dissolved in MeOH and passed through an SCX column washing with MeOH and eluting with 1 N ammonia in MeOH. The solvent was removed under reduced pressure to afford 6-methyl-1,4-diazepan-6-ol as an oil. To this amine in EtOH (3 mL) was added 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (209 mg, 1.29 mmol) and DIPEA (0.9 mL, 5.44 mmol) and the mixture was heated in the microwave at 130° C. for 3 hr. The solvent was removed under reduced pressure. To the crude tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate in DCM (10 mL) was added di-tert-butyl dicarbonate (1.18 g, 5.44 mmol) and DIPEA (0.9 mL, 5.44 mmol). The mixture was stirred at room temperature for 16 hr, the solvent was removed under reduced pressure and the residue dissolved in DCM (30 mL). Water (20 mL) was added and the organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (235 mg, 22% over four steps) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 4.16-3.79 (m, 7H), 3.52-2.81 (m, 4H), 1.70-1.80 (br s, 1H), 1.51 (s, 9H), 1.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH2:29]([OH:32])[C:30]#[CH:31]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:31]#[C:30][CH2:29][OH:32])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=1
Reactant: C#CCO
Reactant: Cc1sc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(C#CCO)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 13.1, the Trifluoro-methanesulfonic acid 2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester was reacted with 2-propyn-1-ol to yield the 3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-yn-1-ol as yellow oil, MS: 346 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:60][C:58]2[S:57][C:47]3[C:48]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=3[N:59]=2)=[O:9])=[CH:5][N:4]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-methoxynicotinic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[NH2:12][NH2:13].C(OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[C:4]1([C:3]2[O:2][CH:1]=[N:12][N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CCOC(OCC)OCC
Product: c1ccc(-c2nnco2)cc1
Temperature: 80 °C

Procedure:
Benzoic acid methyl ester (1.01 g, 7.34 mmol) and hydrazine monohydrate (10 mL) were dissolved in EtOH (20 mL) then heated in a sealed tube to 80° C. for 23 hours. The reaction was allowed to cool and then triethylorthoformate (25 mL) and p-toluenesulfonic acid (0.100 g, 0.526 mmol) were added, the tube was re-sealed, and the reaction was heated to 120° C. for 26 hours. The reaction mixture was then submitted to standard aqueous workup and purified on silica gel (0-70% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]([O:13][C:14]([N:16]([C:24]1[NH:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:15])([CH3:12])[CH3:11]>C(#N)C>[CH3:12][C:10]([O:13][C:14]([N:16]([C:24]1[NH:28][C:27]([CH:29]=[O:30])=[C:26]([Cl:1])[N:25]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:15])([CH3:9])[CH3:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C=O)[nH]1
Temperature: 60 °C
Yield: 11.5 %

Procedure:
N-Chlorosuccinimide (0.346 g, 2.59 mmol) was added to a suspension of bis(1,1-dimethylethyl)(4-formyl-1H-imidazol-2-yl)imidodicarbonate (0.672 g, 2.158 mmol) in acetonitrile (10 mL). The mixture was heated at 60° C. for 2 hrs. The solvent was evaporated. Chromatography of the residue with ethyl acetate:hexane gave the title compound (0.086 g, 11%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.38-10.79 (m, 1H), 9.6 (s, 1H), 1.52 (s, 18H). ES MS: m/z 345
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH:24]1([S:27]([N:22]2[CH2:21][CH2:20][C:3]3([C:7](=[O:8])[N:6]([C:9]4[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=4)[CH2:5][CH2:4]3)[CH:2]([OH:1])[CH2:23]2)(=[O:29])=[O:28])[CH2:26][CH2:25]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2O
Reactant: O=S(=O)(Cl)C1CC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)C1CC1)CC2O

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 2 step A) and cyclopropanesulfonyl chloride. Colourless solid. MS (ESI): 435.3 (MH+)
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].[C:17]([C:20]1[CH:21]=[C:22]([NH:26][NH2:27])[CH:23]=[CH:24][CH:25]=1)([OH:19])=[O:18].C(N(CC)CC)C.C(O)(=O)C>C(Cl)Cl.CO>[NH2:2][C:1]1[N:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:17]([OH:19])=[O:18])[CH:21]=2)[N:27]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(-c2nn(-c3cccc(C(=O)O)c3)c(N)c2C(N)=O)cc1
Yield: 50.5 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol), 3-carboxyphenylhydrazine (304 mg, 2.0 mmol) and triethylamine (2 ml) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 2% acetic acid, 5% methanol in CH2Cl2) to give the title compound as a light yellow solid (340 mg) m.p. 232-235°. δH (d6DMSO) 8.14 (1H, s), 7.93 (1H, d, J 7.9 Hz), 7.86 (1H, d, J 9.0 Hz), 7.64 (1H, t, J 7.8 Hz), 7.47 (2H, d, J 8.1 Hz), 7.30 (2H, d, J 8.1 Hz), 6.55 (1H, br s), 6.53 (1H, br s) and 2.36 (3H, s), carboxyl proton and amino protons not observed. MS (ES, +27V) 337 (MH+, 100%);
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:29]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Cc1cccc(C)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N1c2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A mixture containing 5.0 g of acridan (0.027 mol), 186 mg of Pd(OAc)2 (8.2×10−4 mol), 186 mg of tri-t-butylphosphine (8.2×10−4 mol), 3.97 g of sodium t-butoxide (0.041 mol), and 6.12 g of 1-bromo-2,6-dimethylbenzene (0.033 mol) in 70 mL of dry toluene was stirred under argon at room temperature for 16 h. Since TLC analysis still showed the presence of starting material, the reaction mixture was heated at 85° C. for 3 h. The reaction mixture was cooled, filtered and the precipitate was washed with diethyl ether. The filtrate was passed through a 2″ plug of celite and concentrated to a brown solid. The crude product was chromatographed on silica gel with 5%-20% CH2Cl2 in hexanes to afford 5.1 g (66.2%) of N-(2,6-dimethylphenyl)acridan.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C@:14]12([CH3:24])[C:20]([CH3:22])([CH3:21])[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH2:23].N1C=CC=CC=1>O>[C@:14]12([CH3:24])[C:20]([CH3:21])([CH3:22])[C@@H:17]([CH2:18][CH2:19]1)[CH2:16][C@@H:15]2[NH:23][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC1(C)C2CC[C@@]1(C)C(N)C2
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)[C@H]2CC[C@@]1(C)[C@@H](NC(=O)c1cnc3ccccc3n1)C2
Yield: 50.3 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (R)-(+)-bornylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 140 mg (50%) of (150):
Reaction SMILES: C[N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21][CH3:22])=[O:20])[C@@H:8]([O:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2.C(O)(=O)C.[Mn]([O-])(=O)(=O)=O.[K+]>C(#N)C.O>[CH3:22][O:21][C:19]([C@H:7]1[C@@H:8]([O:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:9][C@H:3]2[NH:2][C@@H:6]1[CH2:5][CH2:4]2)=[O:20]
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
Cocaine (500 mg) was dissolved in a mixture (21 ml) of acetonitrile and water (1:2). Acetic acid (0.5 ml) was added to the solution to adjust its pH to approximately 5. To the solution was added dropwise 21 ml aqueous potassium permanganate (KMnO4=534 mg, 3.78 mmol, 2.05 eq.) over 3 hours. The solution was stirred overnight at room temperature. After removing the resulting precipitate by filtration, potassium carbonate (1050 mg) was added to the filtrate to adjust its pH to approximately 8. The filtrate was extracted with ether three times and dried over anhydrous sodium sulfate overnight. The sodium sulfate was removed out of the extract and ether was distilled off under reduced pressure to give colorless liquid. The liquid was purified by silica-gel thin layer chromatography (hereinafter abbreviated as TLC) using as an eluent ammonia saturated chloroform to give norcocaine (269 mg) of Formula (4):
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].C[Si](C)(C)[C:12]#[C:13][CH3:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Cu]I.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>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:12]#[C:13][CH3:14])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)cncc1Br
Reactant: CC#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC#Cc1cncc(Br)c1C
Temperature: 70 °C
Yield: 15.9 %

Procedure:
3,5-Dibromo-4-methylpyridine (0.50 g, 2.0 mmol), 1-(trimethylsilyl)-1-propyne (0.35 mL, 2.4 mmol), copper(I) iodide (0.11 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.02 mmol) were mixed in toluene (2 mL). The mixture was degassed by a stream of argon for a couple of min. Tetra-n-butylammonium fluoride (1 M in THF) (2.4 mL, 2.4 mmol) was added, and the reaction was heated under N2 at 70° C. overnight. The mixture was partitioned between water containing sat aq. NaHCO3 and EtOAc. The organic phase was dried (MgSO4) and evaporated to give a crude product which was purified by flash chromatography (40 g SiO2, heptane/EtOAc gradient) affording the title compound (0.067 g, 16% yield): 1H NMR (500 MHz, DMSO-d6) ppm 2.15 (s, 3H), 2.46 (s, 3H), 8.48 (s, 1H), 8.61 (s, 1H); MS (ES+) m/z 210 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10](=[O:21])[C:11]3[CH2:12][N:13]([CH2:17][C:18](=O)[CH3:19])[CH2:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:22][CH3:23].[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][CH:18]([CH3:19])[CH2:17][N:13]1[CH2:14][CH2:15][C:16]2[C:7]3[CH:6]=[CH:5][C:4]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[C:8]=3[O:9][C:10](=[O:21])[C:11]=2[CH2:12]1)[CH3:25]
Reactant: COc1ccc2c3c(c(=O)oc2c1OC)CN(CC(C)=O)CC3
Reactant: CCN
Product: CCNC(C)CN1CCc2c(c(=O)oc3c(OC)c(OC)ccc23)C1
Yield: 55.4 %

Procedure:
Prepared by the method described in Example 49 from 1,2,3,4-tetrahydro-7,8-dimethoxy-3-(2-oxopropyl)-5H-benzopyrano[3,4-c]-pyridin-5-one (49.6 g, 0.16 moles) and ethylamine (21.2 g, 0.47 moles). Recrystallization from ethyl acetate/hexane yielded the product (30.7 g) as the free base, mp 125°-127° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17](O)=[O:18].S(Cl)([Cl:23])=O>C=CC(=C)C>[CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17]([Cl:23])=[O:18]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: C=CC(=C)C
Product: CC1(C)[C@H](C(=O)Cl)[C@@H]1/C=C\C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 1.6 g of (1R,cis) 2,2-dimethyl-3[(Z) 3-oxo-3-benzyloxy-1-propenyl]-cyclopropane carboxylic acid, 10 ml of isoprene and 1 ml of thionyl chloride was stirred for 5 hours under a current of nitrogen and then was concentrated to obtain 2 g of (1R,cis) 2,2-dimethyl-3[(Z) 3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylic acid chloride which was concentrated to obtain 2 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylic acid chloride which was used as in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:14])[CH3:15])[C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:25])=[CH:7]2
Reactant: Cc1c(OC(C)C)cc(Br)c2ccncc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(OC(C)C)cc(Br)c2cc[n+]([O-])cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.9 %

Procedure:
To a solution of 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinoline (108e, 1.60 g, 5.71 mmol) in DCM (40 mL) was added m-CPBA (1.47 g, 8.56 mmol) and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was washed with NaHSO3 (aq., 2×20 mL), 10% aq. NaOH (2×20 mL) and brine (2×10 mL), dried over Na2SO4, and concentrated under vacuum to give 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinoline 2-oxide (108f, 1.3 g, 77%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([CH3:18])[N:17]=[C:4]2[N:3]=1.N>ClCCl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[C:16]([CH3:18])[N:17]=[C:4]2[N:3]=1
Reactant: Cc1nc2nc(Cl)c(-c3ccccc3)c(Cl)n2n1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2nc(Cl)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34.5 g 5,7-dichloro-2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine is dissolved in 500 ml dichloromethane. 500 ml brine, 250 ml ammonia solution 25% w/w and 34.0 g zinc powder are added and the mixture is stirred at room temperature for 1 h. The reaction mixture is filtrated over kieselgur and is washed with dichloromethane and water. The organic phase is separated and the water phase is extracted with dichloromethane. The combined dichloromethane phase is dried over Na2SO4 and the solvent is evaporated. The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate) to yield the desired compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1.[OH:24]O>S(=O)(=O)(O)O>[O:24]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Fc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Reactant: OO
Agent: O=S(=O)(O)O
Product: O=S1CCN(c2nc(N3CCNCC3)cc3c(F)cccc23)CC1
Yield: 31 %

Procedure:
1-(1-Oxido-thiomorpholino-3-piperazino-5-fluoro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-fluoro-isoquinoline by oxidation with hydrogen peroxide in dilute sulfuric acid. M.p. 213°-215°C (from n-propanol/petroleum ether). Yield: 31% of theory.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:23]([F:24])=[CH:22][C:10]3[NH:11][C:12]([O:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C([SiH](CC)CC)C.[CH:45]([O:48][P:49]([O-:54])[O:50][CH:51]([CH3:53])[CH3:52])([CH3:47])[CH3:46]>C1(C)C=CC=CC=1.CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:45]([O:48][P:49]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:12]2[NH:11][C:10]3[CH:22]=[C:23]([F:24])[C:7]([C:4]4[CH:5]=[CH:6][C:1]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:2][CH:3]=4)=[CH:8][C:9]=3[N:13]=2)[CH:16]=1)(=[O:54])[O:50][CH:51]([CH3:53])[CH3:52])([CH3:47])[CH3:46]
Reactant: Fc1cc2[nH]c(Oc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Reactant: CC(C)OP([O-])OC(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(OC(C)C)c1cccc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)c1
Reaction time: 0.12 h

Procedure:
To a microwave reactor vial was added compound 13-7 (107 mg, 0.23 mmol), PdCl2(dppf) (34 mg, 0.047 mmol), triethylamine (0.1 mL, 0.69 mmol), triethylsilane (15 μL, 0.092 mmol), diisopropylphosphite (46 μL, 0.28 mmol) in 3 mL of toluene and 0.5 mL of DMF. The reaction was run in a microwave reactor for 7 min at 140° C. The reaction mixture was diluted with EtOAc (50 mL) and washed three times with 50 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting with EtOAc/Hexanes=4/1) to yield title compound 13-8 as a brown oil.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)(=O)=O.[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28][CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:7]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: Sc1ccccc1
Product: O=C(OCc1ccccc1)N1CCCC(Sc2ccccc2)C1

Procedure:
The entitled compound was produced according to the method of Example 1(1) but using benzyl 3-[(methylsulfonyl)oxy]piperidine-1-carboxylate produced according to the method described in a known reference (WO96/39407) and thiophenol.
Reaction SMILES: [CH3:1][C:2]1([C:5]([N:7]2[CH2:16][C:15]3[NH:14][C:13]4[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([O:23]C)=O)[C:12]=4[C:11](=O)[C:10]=3[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3]1.O.[NH2:27][NH2:28]>>[CH3:1][C:2]1([C:5]([N:7]2[CH2:16][C:15]3[NH:14][C:13]4[CH:17]=[CH:18][CH:19]=[C:20]5[C:21](=[O:23])[NH:27][N:28]=[C:11]([C:12]=45)[C:10]=3[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1(C)CC1)C3
Solvent: O
Product: CC1(C(=O)N2CCC3=C(C2)Nc2cccc4c(=O)[nH]nc3c24)CC1

Procedure:
The target product was prepared from methyl 2-(1-methylcyclopropanecarbonyl)-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate and hydrazine hydrate according to the same procedure described as in Example 1 (step 4). 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.6 (s, 1H), 7.62-7.64 (m, 1H), 7.47-7.49 (m, 1H), 7.24-7.26 (m, 1H), 4.41 (bs, 2H), 3.85 (bs, 2H), 2.42 (bs, 2H), 1.28 (s, 3H), 0.84 (bs, 2H), 0.60 (bs, 2H). MS (ESI) m/e [M+1]+323.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([OH:32])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(OCC)C>[C:7]([Cl:2])(=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)O
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus pentachloride (0.123 mol, 25.6 g) was added gradually to a solution of nervonic acid (available from Aldrich Chemicals) (0.123 mol, 45.0 g) in dry ethyl ether (225 mL, C=200 g.L−1). The mixture was stirred at room temperature under nitrogen for 3 h and concentrated to dryness to yield z-15-tetracosenoyl chloride as pale yellow, fairly viscous oil.