Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].[F-].[K+].COC(=O)CCCC(C1C=CC(C(OC2C=NC(C3C=CC(C(C)(C)C)=CC=3)=CC=2)CCC(C)(C)C)=CC=1)=O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25]([C:38]3[CH:39]=[CH:40][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=3)=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(Cl)nc2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: COC(=O)CCCC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)nc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)nc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-{4-[1-(6-chloro-pyridin-3-yloxy)-4,4-dimethyl-pentyl]-benzoylamino}-propionic acid methyl ester (84 mg, 0.19 mmol) in toluene:water (1:1) (2 mL) is added palladium tetrakis triphenylphosphine (22.47 mg, 0.1 mol %), 4-tert-butylphenylboronic acid (58 mg, 0.39 mmol). The reaction is purged with nitrogen and heated to reflux and the potassium fluoride (23 mg, 0.39 mmol) is added. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and then Celite is added, followed by water. This mixture is then filtered through a pad of Celite. The solution is separated in a seperatory funnel and the organic layer is washed with 0.1N sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The 5-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-phenyl)-5-oxo-pentanoic acid methyl ester (80 mg, 0.15 mmol) is purified by flash column chromatography.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1CCN(C2C3CNC(C4N=CC=CN=4)CC=3N=C(C3C=CC(N)=CC=3)N=2)C[CH2:32]1.[NH2:60][C:61]1[O:65][N:64]=[C:63]([CH3:66])[CH:62]=1.C1(CN)CC1>>[CH3:66][C:63]1[CH:62]=[C:61]([NH:60][C:32]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[N:26]=[CH:27][CH:28]=[CH:29][N:30]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:15][CH:16]=2)=[O:31])[O:65][N:64]=1
Reactant: Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC(c2ncccn2)C3)cc1
Reactant: Cc1cc(N)on1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Agent: NCC1CC1
Product: Cc1cc(NC(=O)Nc2ccc(-c3nc4c(c(N5CCOC[C@@H]5C)n3)CCN(c3ncccn3)C4)cc2)on1

Procedure:
The title compound lf was prepared by the general procedure of Example 30 substituting (S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline for 4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)aniline and 5-amino-3-methylisoxazole for cyclopropylmethylamine. LC-MS: m/z=+528 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[CH3:10]>CS(C)=O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:4][C@H:14]1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)=[O:25])[CH3:10]
Reactant: CCOC(=O)C=Cc1ccc2ncccc2c1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a suspension of sodium hydride (71 mg, 1.76 mmol) in DMSO (3 mL) under nitrogen atmosphere was added trimethylsulfoxonium chloride (261 mg, 2.03 mmol). After stirring at room temperature for 30 minutes, a solution of 3-quinolin-6-yl-acrylic acid ethyl ester (200 mg, 0.881 mmol) in DMSO (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2.5 h and quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine (3×) and adsorbed on silica gel. Purification on silica gel with 0-80% gradient of ethyl acetate in hexane provided 126 mg of product as a white solid. NMR 500 MHz (DMSO) δ 1.22 (t, 3H), 1.55 (m, 2H), 2.10 (m, 1H), 2.64 (m, 1H), 4.13 (q, 2H), 7.50 (dd, 1H), 7.58 (dd, 1H), 7.80 (d, 1H), 7.93 (d, 1H), 8.26 (dd, 1H), 8.84 (dd, 1H); MS (m/z) 242 [M+H+]+.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OC=O)(=[O:18])C.C(O)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH:16]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: CC(=O)OC=O
Reactant: C(=NNc1ccccc1)c1cccnc1
Solvent: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(N=Cc1cccnc1)c1ccccc1
Reaction time: 8 h

Procedure:
9.85 g of 3 (prepared as described in Example 3) was dissolved in 50 ml of dry methylene chloride. 15 ml of formic acetic anhydride (prepared by mixing the appropriate amounts of formic acid and acetic anhydride) was added. The mixture was allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in ether. The solution was washed with sodium bicarbonate solution, dried (Na2SO4) and the solvent evaporated to give 4, as a white crystalline solid, mp 129°-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][NH2:14].[CH3:15][CH2:16][O:17][C:18]([CH:20]([C:24]([CH3:26])=O)[C:21]([CH3:23])=O)=[O:19].C(Cl)Cl>C(Cl)Cl.CO>[CH2:16]([O:17][C:18]([C:20]1[C:21]([CH3:23])=[N:14][N:13]([C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:24]=1[CH3:26])=[O:19])[CH3:15]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: COc1ccc(C(F)(F)F)cc1NN
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nn(-c2cc(C(F)(F)F)ccc2OC)c1C
Yield: 58 %

Procedure:
In analogy to the procedure described in Example 38A], (2-methoxy-5-trifluoromethyl-phenyl)-hydrazine and ethyl diacetoacetate gave, after flash column chromatography (CH2Cl2 to CH2Cl2:MeOH 99:1), the title compound in 58% yield as a light green solid. MS: 343.1 (MH+).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.C(OP(OCC)OCC)C.[CH:26](=O)[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:12]([O:11][C:9](=[O:10])[C:8]1[CH:14]=[CH:15][C:5](/[CH:4]=[CH:26]/[C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:6][CH:7]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: O=Cc1ccco1
Agent: CCOP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C/c2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
60% Sodium hydride (0.48 g, 12 mmol) was suspended in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere, and diethyl 4-ethoxycarbonyl benzylphosphonate (3.6 g, 12 mmol) prepared from ethyl 4-bromomethylbenzoate and triethylphosphite according to the methods as similar to those of Manufacturing Example 93-1-1 was added at room temperature and stirred for 30 minutes at room temperature. Furfural (1 g, 10.4 mmol) was then added at room temperature, and stirred for 2 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate on an ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:20) to obtain the title compound (1.07 g, 42%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25]C(OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[S:13][N:12]=1.C[C:39]([O-:42])(C)C.[K+].BrCCOC>C1COCC1>[CH3:39][O:42][CH2:25][CH2:24][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Reactant: CC(C)(C)[O-]
Agent: COCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 100 %

Procedure:
(S)-Methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (2.0 g, 3.68 mmol) was dissolved in THF (20 mL) and nitrogen was bubbled through the solution for 5 minutes. Potassium 2-methylpropan-2-olate (1M in THF, 11.0 ml, 11.0 mmol) was added and the reaction was stirred at ambient temperature for 1 minute. 1-Bromo-2-methoxyethane (0.518 ml, 5.52 mmol) was added and the reaction was stirred at ambient temperatures for 20 minutes. The reaction was partitioned between EtOAc and aqueous NH4Cl, dried, filtered and concentrated. The residue was purified over silica gel (100%) EtOAc) to afford (S)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (1.9 g, 3.68 mmol, 100% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[CH:29]=[CH:28][O:27][CH:26]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Reactant: BrCc1ccoc1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ccc(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 8 g (26.4 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 87, part B) and 30 mL (30 mmol) of a freshly prepared 1M solution in ethyl ether of 3-bromomethyl-furan. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 9.9 g (99% of yield) of 4-(1-furan-3-ylmethyl-5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.CCOC(C)=O>[NH:29]([C:30]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCN(C(=O)Nc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To an ice cooled solution of 4-(piperidin-4-yloxy)benzaldehyde (2 g) and triethylamine (1.35 ml) in tetrahydrofuran (20 ml) was added phenyl isocyanate (1.3 ml). The mixture was stirred at room temperature for 3 h. At the end of this time, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3 solution followed by water, dried (Na2SO4) and concentrated to get 3.1 g (99%) of the title product as a gummy solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:23]C)[N:13]3[CH2:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([NH2:25])[N:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][O:19]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CCC1CCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-9-[2-(tetrahydro-2-furanyl)ethyl]-9H-purin-6-amine (88 mg, 0.253 mmol) in methanol (10 ml) at room temperature was added 4M HCl in 1,4 dioxane (2.106 ml, 8.42 mmol) to give a pale straw coloured solution. The reaction mixture was stirred at ambient temperature overnight (16 hours) and then loaded in methanol onto a 5 g aminopropyl SPE cartridge and eluted with methanol. The filtrate was evaporated on a nitrogen blowdown unit to give the title compound as a white solid (41 mg).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1)(=[O:5])=[O:4].O1CC[CH2:19]OO1>CS(O)(=O)=O.FC(F)(F)C(O)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:8]2=[C:7]3[C:14]=1[CH2:1][N:2]([CH3:19])[S:3](=[O:4])(=[O:5])[C:6]3=[CH:10][S:9]2
Reactant: C1COOOC1
Reactant: CNS(=O)(=O)c1csc2ccc(Cl)cc12
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(Cl)ccc3scc(c23)S1(=O)=O
Temperature: 35 °C
Reaction time: 3 h

Procedure:
0.60 g of 5-chloro-benzo[b]thiophene-3-sulphonic acid-methylamide are dissolved in 8.9 ml of methanesulphonic acid at 35° C. and combined with a solution of 0.09 g trioxane in 2.7 ml trifluoroacetic acid. After 3 h stirring at 35° C. the reaction mixture is poured onto 100 ml of ice water and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried with Na2SO4, evaporated down in vacuo and then purified by chromatography. Yield: 0.30 g. M.p.: 196° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][CH3:13])[C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCCCC)CCC.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[NH2:9][CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1([N:2]([CH3:1])[CH2:10][CH2:11][O:12][CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COCCN(C)C1(C#N)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(C)C1(C(N)c2ccccc2)CCCC1
Yield: 42 %

Procedure:
The title compound (1.22 g; 42%) was prepared from 1-{methyl[2-(methyloxy)ethyl]amino}cyclopentanecarbonitrile D35 (2.0 g; 11 mmol), and phenyllithium in di-n-butylether (6.7 ml of 1.8M solution; 12 mmol) in THF (25 ml), followed by reaction with sodium borohydride (1.25 g; 33 mmol) in methanol (25 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS). Found 263 (MH+). C16H26N2O requires 262. Ret. time 1.57 min.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:6][S:7][CH2:8][CH:9]([CH3:24])[C:10](=[O:23])[CH2:11][CH2:12]/[C:13](/[CH3:22])=[CH:14]\[CH2:15][CH2:16]/[C:17](/[CH3:21])=[CH:18]\[CH2:19][OH:20])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[C:1]([NH:4][C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:6][S:7][CH2:8][CH:9]([CH3:24])[C:10](=[O:23])[CH2:11][CH2:12]/[C:13](/[CH3:22])=[CH:14]\[CH2:15][CH2:16]/[C:17](/[CH3:21])=[CH:18]\[CH2:19][O:20][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H](CSCC(C)C(=O)CC/C(C)=C\CC/C(C)=C\CO)NC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CSCC(C)C(=O)CC/C(C)=C\CC/C(C)=C\COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.5 g of methyl N-acetyl-3-[[(6Z,10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]alaninate dissolved in 15 mil of methylene chloride is treated at 0° with 39 ml of pyridine and 30 ml of acetic anhydride. The solution is stirred at room temperature for 20 hours. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The crude product is chromatographed on silica gel with ether-methanol 50:1. There is obtained methyl N-acetyl-3-[[(6Z,10Z)-12-acetoxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]alaninate which exhibits the following absorption bands in the IR spectrum: 1738 cm-1, 1713 cm-1, 1664 cm-1, 1438 cm-1, 1412 cm-1, 1236 cm-1, 1117 cm-1.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]([CH2:18][CH3:19])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]([CH2:18][CH3:19])[C:3](=[O:20])[CH:2]([NH:1][C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A solution of crude 3(R,S)-amino-5-cyclopentyl-l,3-dihydro-1-ethyl-2H-1, 4-benzodiazepin-2-one [Example 5, Step 5] (0.23 g, 0.92 mmol) in dry tetrahydrofuran (15 ml) under an atmosphere of nitrogen, at 0° C., was treated with triethylamine (0.11 ml, 0.92 mmol) followed by a solution of 4-nitrophenyl chloroformate (184 mg, 0.92 mmol) in tetrahydrofuran (10 ml). After stirring at ambient temperature for 30 min the solid which precipitated was removed by filtration and the tiltrate concentrated in vacuo to afford the title compound (0.32 g, 79%) as a colourless solid. mp 136°-138° C. 1H NMR (360 MHz, CDCl3) δ 0.9 (3H, t, J=7 Hz), 1.0-2.2 (8H,m), 3.50 (1H, p, J=7 Hz), 3.70 (1H, m), 4.18-4.28 (1H, m), 5.14 (1H, d, J=8 Hz), 7.30-8.20 (8H, m), 9.12 (1H, d, J=8 Hz).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.ClCCl>C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCN)cc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCNS(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Methanesulfonic anhydride (0.19 g, 1.1 mmol) was added to a stirring solution of 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 1.07 mmol), dichloromethane (75 ml) and acetonitrile (100 ml). The reaction was maintained at room temperature for 60 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethanemethanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.3 g of N-[4-(4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl]methanesulfonamide as a white solid, m.p. 78.1-79.5° C. 1H NMR (300 MHz, DMSO-d6) δ7.99 (d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.2 Hz, 1H), 7.42 (m, 1H), 7.27-7.21 (m, 3H), 6.98 (t, J=5.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.58 (broad s, 2H), 4.45 (broad s, 2H), 4.33 (s, 2H), 3.72 (s, 3H), 2.87 (m, 5H), 1.55 (broad s, 2H); MS (CI) m/e 454 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(NC(C)C)(C)C.[OH:48][NH:49][C:50](=[NH:59])[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1>CN(C)C=O>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[C:14](=[O:16])[NH:59][C:50](=[N:49][OH:48])[C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=N)NO)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(=NO)NC(=O)[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
23 mg (0.1 mmol) of Boc-D-Pipecolic Acid were treated with 0.1 mmol [Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate (HATU) and Diisopropylamine (DIPEA) in 1 ml Dimethylforamide (DMF) for 10 min. 17 mg (0.1 mmol) of N-Hydroxy-4-methoxy-benzamidine were added and the reaction stirred at room temperature for 20 min. The product was not further characterized.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: F[C@H]1CCN(CCCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CC[C@H](F)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.4 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one (0.51 g, 1.6 mmol) in DMSO (5.0 mL) was added (S)-1-(2-chloroethyl)-3-fluoropyrrolidine (0.24 g, 1.6 mmol) and Cs2CO3 (3.1 g, 9.5 mmol). The reaction mixture was stirred at ambient temperature for 18 h, and then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×20 mL). The organic extracts were washed with brine (3×20 mL) and dried (Na2SO4). Purification by flash chromatography (silica gel, CH2Cl2/80:18:2 CH2Cl2/MeOH/NH4OH, 100.0 to 0:100), followed by additional flash column chromatography (silica gel, CH2Cl2/10% MeOH in CH2Cl2, 100:0 to 10:90), followed by treatment with activated charcoal, followed by final purification by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (58.3 mg, 8%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.45-7.37 (m, 6H), 7.31-7.30 (m, 1H), 6.12-6.10 (m, 2H), 5.16 (dt, J=55.5, 4.5 Hz, 1H), 5.07 (s, 2H), 4.58 (t, J=7.0 Hz, 2H), 3.01 (br m, 2H), 2.97-2.93 (m, 2H) 2.92-2.90 (m, 1H), 2.56 (br s, 1H), 2.17-2.03 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.9 min.