Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)Nc2cccc(C#N)c2)c2nc(C3CC3)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-cyano-phenyl)-amide (113 mg, 0.26 mmol) in CH2Cl2 (2.6 mL) was added trifluoroacetic acid (1 mL). Stirred at room temperature for 2 h then neutralized with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was dissolved in EtOH and NaOAc (0.7 g) was added. The reaction mixture was stirred at 60° C. overnight then cooled to room temperature and water and EtOAc were added. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (MeOH/CH2Cl2) to give 22 mg (28%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-cyano-phenyl)-amide. MS: (M+H)+=304; mp=272.0-274.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=O)[CH2:9]1.O.[OH-].[Na+]>O1CCCC1>[C:14]1([CH2:13][N:12]2[CH2:8][CH2:9][CH:10]([CH2:20][NH:22][CH2:23][CH2:24][CH3:25])[CH2:11]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 8.2 g (0.2 mole) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran was added portionwise, 12.0 g (45.6 mmole) of solid 5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide. When the addition was complete, the reaction mixture was stirred at room temperature for 18 hours and then at reflux for two hours. After cooling to room temperature, the mixture was treated dropwise, successively, with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml of water, titrating the final addition to produce a granular precipitate. The solid was removed by filtration, washed with tetrahydrofuran and the filtrate evaporated in vacuo to give 9.6 g of 1-(phenylmethyl)-N-propyl-3-pyrrolidine methanamine, as a heavy syrup.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27]([OH:29])=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1.[CH3:44][Si](C=[N+]=[N-])(C)C>CO>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27]([O:29][CH3:44])=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(=O)O)CC1
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid 8 (40 mg, 0.07 mmol) in methanol (2 mL) was added (trimethylsilyl)diazomethane (0.35 mL, 2.0 M in hexanes). The resulting mixture was further stirred for 30 minutes. After evaporation of solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate 9 as an oil (40 mg, quant.). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.54 (s, 1H), 7.45-7.41 (m, 1H), 7.37-7.34 (m, 2), 7.29-7.21 (m, 5H), 7.18-7.10 (m, 2H), 4.63-4.53 (m, 1H), 4.21-4.18 (m, 1H), 3.86 (br, 3H), 3.44 (br, 1H), 3.24 (br, 3H), 3.08 (br, 1H), 2.53 (s, 3H), 2.36-2.34 (m, 3H), 1.91-1.71 (m, 11H), 1.59 (d, J=7.0 Hz, 2H). HRMS m/z (M+H)+ calcd 591.3335; obsd 591.3353.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](Cl)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: c1c[nH]cn1
Reactant: CCCCCC(=O)Cl
Solvent: Cc1ccccc1
Product: CCCCCC(=O)n1ccnc1

Procedure:
The method of Pfander and Laederach [H. Pfander and M. Laederach, Carbohyd. Res. 99(2), 175-79 (1982)] was used. 1-Hexanoylimidazole was prepared by stirring 2 equivalents of imidazole with 1 equivalent hexanoyl chloride in toluene solution. The mixture was filtered and concentrated to a low-melting solid. This product, 1-hexanoylimidazole, was further purified by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH3:14])[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH3:14])[C:10]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: COC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
Example 39 was prepared from (3,4-dichlorophenyl)(methoxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.02–7.94 (m, 1H), 7.54 (d, 2H, J=10.1 Hz), 7.41 (d, 1H, J=8.5 Hz), 7.34–7.19 (m, 4H), 6.97 (d, 1H, J=7.0 Hz), 4.56 (s, 1H), 3.83 (s, 3H), 3.09–3.01 (m, 2H), 2.55–2.39 (m, 4H), 2.17 (s, 1H), 2.08–1.95 (m, 3H), 1.91–1.77 (m, 4H), 1.74–1.65 (m, 2H), 1.22 (d, 6H, J=6.6 Hz); ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1[N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1c1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 468 mg (5.5 mmol) of 2-pyrrolidone (Fluka, Buchs, Switzerland) in 10 ml of DMF at 0° C. are added 240 mg (5.5 mmol) of 55% NaH in oil. The reaction mixture is stirred for 30 min at 0° C. and for 30 min at rt. After this time, 795 mg (5 mmol) of 3,4-difluoronitrobenzene (Aldrich, Buchs, Switzerland) are added and the reaction mixture is stirred for 1 h at rt. The reaction mixture is quenched with 1 M aqueous HCl and extracted with EtOAc (2×). The organic layers are washed with aqueous sat. NaHCO3 and with brine (3×), dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 5:1 to 1:3) to give the title compound as a solid. ES-MS: 225 (M+H)+; analytical HPLC: tret=2.99 minutes (Grad 1).
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13].C[O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)=O>C(O)(=O)C>[CH2:16]([O:15][C:12](=[O:14])[CH2:13][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)=[O:19])[CH3:17]
Reactant: COC(=O)c1cccc(C)n1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cccc(C)n1
Temperature: 92 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
Stir a mixture of sodium ethoxide (90 g, 1.32 mol, 2 eq), toluene (0.5 L, 5 vol), and ethyl acetate (0.2 L, 1.98 mol, 3 eq) in a 2 L flask equipped with reflux condenser, mechanical stirrer, and nitrogen inlet. After 1 h, add 6-methyl-pyridine-2-carboxylic acid methyl ester (Cheung, Y, Tetrahedron Lett. 1979, 40, 3809-10; 100 g, 0.66 mol). Heat the mixture at reflux (92° C.) for 20 h. Cool the mixture to room temperature and acidify with glacial acetic acid to pH 6. Wash the resulting gel with water (0.5 L). Separate the layers and extract the aqueous layer with toluene (1×0.5 L) Dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield the subtitled product (154 g) as a dark oil in 86% purity by HPLC analysis. MS ES+ m/e 208 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:13]C=O.[OH-].[K+].CO>O>[CH3:12][C:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH2:13])[CH:4]=[CH:5][CH:6]=1)([CH3:11])[CH2:9][CH3:10]
Reactant: CCC(C)(C)c1cccc(NC=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)c1cccc(N)c1C

Procedure:
2,21 g (10.77 mmol) N-(2-methyl-3-(1,1-dimethylpropyl)phenyl)form-amide, 1,42 g (21.54 mmol) 85% potassium hydroxide and 9 ml methanol are heated under stirring at reflux temperature for 15 hours. After cooling 100 ml of water is added and the reaction mixture is extracted with ethylacetate. After drying of the organic phase over sodium sulfate and evaporation of the solvent in a water jet vacuum, the product is purified by destillation (bp. ca. 70° C., 13,33 Pa). This gives 1.7 g of 2-Methyl-3-(1,1-dimethylpropyl)phenylamine in the form of a colourless oil (89% of theory).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[CH:16]=2)[N:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:9])[CH:19]=[CH:18]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(Cl)ccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2cc(CBr)ccc2n1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
N-Bromosuccinimide (12.9 g, 72.5 mmol) and benzoyl peroxide (0.33 g, 1.30 mmol) are added to a solution of 2-chloro-6-methyl-quinoline (12.0 g, 67.5 mmol) in carbon tetrachloride (300 mL). The mixture is heated at reflux for 6 hours. At this time, the resulting mixture is cooled to room temperature, filtered, washed with CH2Cl2 and concentrated in vacuo. The crude residue is recrystallized from 50% EtOAc/hexanes to yield the title compound (8.80 g, 34.3 mmol) as a beige crystalline solid. 1H NMR (CDCl3, 300 MHz) δ8.08 (d, 1H), 8.02 (d, 1H), 7.83 (s, 1H), 7.77 (dd, 1H), 7.40 (d, 1H), 4.65 (s, 2H). MS (EI): m/z 256, 258 (M+), Cl pattern.
Reaction SMILES: C(=O)([O-])OCC[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([N:38]([CH2:5]/[CH:6]=[CH:7]/[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)[S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: N#Cc1cccc(/C=C/CCCOC(=O)[O-])c1
Reactant: CCS(=O)(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a suspension of [3-(3-cyanophenyl)-2-(E)-propenyl]ethyl carbonate (1.04 g) and N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]ethanesulfonamide (1.15 g) in tetrahydrofuran (9 ml) were added tris(dibenzylideneacetone)palladium chloroform complex (0.077 g) and triphenylphosphine (0.039 g) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=8/1 as an eluant to give the desired compound (1.57 g, yield quantitative) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[N:16](C)[CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH+]1C=CC=CC=1>O>[CH2:1]([N:8]1[C:9](=[O:18])[CH:10]2[NH:16][CH:13]([CH2:12][CH2:11]2)[C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1

Procedure:
A mixture of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo-(3.2.1)octane (U.S. Pat. No. 3,328,396) (1.05 g) and pyridinium hydrochloride (5 g) was heated in an oil-bath at 220° C. for 25 minutes. After cooling, the mixture was taken up with water (30 mL) and extracted with ether. The organic layer was dried over magnesium sulfate, evaporated to give 0.45 g of crude product which was chromatographed over silica gel using dichloromethane-ethyl acetate 80:20 as eluent to give 0.3 g of crystallized titled product. MP 72° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH:16](I)([CH3:18])[CH3:17].O>CN(C=O)C>[CH:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(C)C)c2ccccc12
Reaction time: 7 h
Yield: 77.8 %

Procedure:
In DMF (8.0 ml) was suspended sodium hydride (60% in oil, 275.2 mg, 6.881 mmol). To the resulting suspension was added methyl indole-3-carboxylate (401.8 mg, 2.294 mmol) at 0° C. under stirring. After stirring for further 45 minutes at the same temperature, isopropyl iodide (0.34 ml, 3.440 mmol) was added to the reaction mixture. Stirring was then conducted for 1.5 hours at 0° C. and for 7 hours at room temperature. Water was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate. The extract was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1, v/v) eluate fractions, methyl 1-isopropylindole-3-carboxylate (387.6 mg, 78%) was obtained as a light yellow oil.
Reaction SMILES: II.[CH:3]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[CH:4]2[C:5](=[O:14])[CH2:6][C:7]1=[O:13].[CH3:15]O>>[CH3:15][O:14][C:5]1[CH:4]2[CH:8]([CH:9]3[O:12][CH:3]2[CH2:11][CH2:10]3)[C:7](=[O:13])[CH:6]=1
Reactant: CO
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Agent: II
Product: COC1=CC(=O)C2C3CCC(O3)C12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (0.10 g, 0.38 mmol) is added to a solution of (1RS,2SR,6RS,7SR)-10-oxa-tricyclo[5.2.1.02,6]decane-3,5-dione (2.1 g, 12.65 mmol) in methanol (50 ml) and the reaction mixture is stirred for 2 hours at room temperature. The solvent is then removed under reduced pressure, dichloromethane is added and the organic layer is washed with saturated aqueous sodium thiosulfate solution, water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give (1RS,2SR,6RS,7SR)-5-methoxy-10-oxatricyclo[5.2.1.02,6]dec-4-en-3-one and used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([C:18]([OH:20])=O)[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:55][O:56][C:57]1[CH:58]=[C:59]([CH:61]=[CH:62][CH:63]=1)[NH2:60]>CN(C=O)C>[CH3:55][O:56][C:57]1[CH:58]=[C:59]([NH:60][C:18]([C:2]2([CH3:1])[CH2:7][CH2:6][N:5]([C:8]3[C:9]4[C:16]([CH3:17])=[CH:15][NH:14][C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:4][CH2:3]2)=[O:20])[CH:61]=[CH:62][CH:63]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)C2(C)CCN(c3ncnc4[nH]cc(C)c34)CC2)c1
Reaction time: 8 h
Yield: 328.5 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from step B (0.020 g, 0.073 mmol) in DMF (1 mL) were added BOP reagent (0.065 g, 0.15 mmol), triethylamine (0.019 mL, 0.15 mmol), and 3-methoxyaniline (0.012 mL, 0.11 mmol). The reaction was stirred overnight, and then concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.091 g, 33%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][C:8](=[O:16])[NH:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COCCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COCCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc2C1
Yield: 15.2 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-7-methoxy-4-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (80 mg, 0.30 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (90 mg, 0.30 mmol) were coupled to afford (1S,2S,3R,4R)-3-{5-chloro-2-[7-methoxy-4-(2-methoxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (24 mg, 14%) as a tan foam following reverse-phase preparative chromatography; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.77 (s, 1H), 6.96 (s, 1H), 6.32 (m, 1H), 6.09 (m, 1H), 4.38 (m, 1H), 4.22 (m, 1H), 4.16 (m, 1H), 3.84 (m, 5H), 3.77 (s, 2H), 3.44 (m, 4H), 3.41 (s, 3H), 3.04 (s, 1H), 2.80 (s, 1H), 2.53 (d, J=8 Hz, 1H), 1.57 (d, J=8 Hz, 1H); MS (m/e) 528 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:19]>CO>[NH2:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: N
Solvent: CO
Product: Nc1ncnc2ccc(-c3ccc(F)cc3)cc12

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and a 7 N ammonia solution in methanol in 84%, using the procedure described for example 37. The product was characterized by its mass spectrum as follows: MS (m/z): 240 ([M+H]+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=O.CCOC(C)=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1N
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A solution of 43A (3.35 g, 11.7 mmol) in MeOH (30 mL):EtOAc (30 mL) was degassed with argon for 30 minutes. The resulting solution was treated with 10% Pd/C (335 mg) and stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a pad of celite and concentrated to afford 43B (2.6 g, 87%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.BrCCCCCCC.C(O)(=O)C.O1CCCC1>[CH3:13][CH:12]=[CH:11][CH:10]([OH:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C/C=C/C=O
Reactant: CCCCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC=CC(O)CCCCCCC
Temperature: 10 °C
Yield: 82.1 %

Procedure:
Under an atmosphere of nitrogen the flask is charged with 121 g magnesium and 720 g tetrahydrofuran. The Grignard-reaction is started with 5 g bromo-heptane. Then, a solution of 908 g bromo-heptane in 1000 g toluene is added dropwise within 260 minutes under stirring. The reaction mixture is kept between 55 and 60° C. The resulting dark solution is cooled to 10° C. and a solution of 357 g crotonaldehyde in 500 g toluene is added dropwise within 105 minutes, during which the pot temperature is kept between 10 and 20° C. with an ice-water bath. The resulting grey-brown suspension is continued to stir for 20 minutes at max. 20° C. and then poured, under vigorous stirring, into a mixture of 2 kg ice and 1 l aqueous saturated ammonium chloride solution. The mixture is diluted with 4 l water and buffered with 300 ml acetic acid. The phases are separated. The organic layer is washed with 4 l and 2 l hot water. The organic phase is concentrated in vacuo to give 864 g crude product as a pale yellow oil. This is distilled at 0.1 mbar over a 10 cm-Raschig ring column. Fractions boiling between 85 and 90° C. were collected to give 709 g undec-2-en-4-ol.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:21][N:20]([CH3:22])[C:12]1([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CN(C)C1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C1(c2cccs2)CCNCC1
Yield: 88.6 %

Procedure:
HCl gas was passed through a solution of 10 g (1 eq.) tert-butyloxycarbonyl-4-(dimethylamino)-4-(thiophen-2-yl)piperidine in chloroform at 0° C. for ±1 h. Once the conversion was complete, 200 ml water were added to the reaction mixture, it was adjusted to a pH of ˜8 with Na2CO3 and then extracted with 15% IPA/CHCl3. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 6 g (89%) of product were obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reaction time: 2 h

Procedure:
4,5-Dihydro-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3amine (50 g) was dissolved in dichloromethane (500 ml) and treated portionwise with activated manganese dioxide (50 g) over one hour. The mixture was stirred for a further 2 hours then filtered through bentonite and chromatographed on a silica column with dichloromethane as eluant. The eluants were evaporated to dryness and the title compound recrystallised from aqueous ethanol as an off-white solid (40 g), mp 96°-98°.