Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:25]([CH2:24][Cl:23])(=[O:27])=[O:26])=[CH:7][CH:8]=1
Reactant: CSc1ccc(NCc2cccnc2)cc1
Reactant: O=S(=O)(Cl)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CSc1ccc(N(Cc2cccnc2)S(=O)(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 3.4 g. portion of 3-(4-methylthiophenylaminomethyl)pyridine was dissolved in 25 ml. of dichloromethane, and 4.1 g. of potassium carbonate and 4.5 g. of chloromethanesulfonyl chloride were added. The mixture was stirred at ambient temperature for 4 days, and then 20 ml. of aqueous sodium bicarbonate was added. The mixture was extracted with 15 ml. of dichloromethane, and the organic phase was washed with aqueous sodium bicarbonate, dried and evaporated to an oil. The oil was dissolved in dichloromethane and chromatographed on silica gel, eluting with dichloromethane. Combination of the product-containing fractions gave 1.6 g. of the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([O:12][CH3:13])=[O:11].CI.[CH3:16]C(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:16][C:2]1([C:10]([O:12][CH3:13])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1Cc2ccccc2O1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)Cc2ccccc2O1
Temperature: 25 °C

Procedure:
To a solution of methyl 2,3-dihydrobenzofuran-2-carboxylate (Step A, 1.0 g, 5.5 mmol) and methyl iodide (1.8 mL, 28 mmol) in 20 mL of anhydrous tetrahydrofuran at −78° C. was added potassium tert-butoxide (1 M in tetrahydrofuran, 8.4 mL, 8.4 mmol). The reaction was allowed to warm to room temperature overnight, and the resulting mixture was diluted with ethyl acetate (100 mL), washed with aqueous saturated ammonium chloride (100 mL) and water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography eluted with 2-5% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.16 (d, 1H), 7.12 (t, 1H), 6.86 (t, 1H), 6.76 (d, 1H), 3.75 (s, 3H), 3.58 (d, 1H), 3.17 (d, 1H), 1.66 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=[O:3])[CH3:2].C1(N)CCCC1.C([BH3-])#N.[Na+].NC(N)=O.[CH:25]1([N:30](C2CCCC2)[C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=C1N=CC=N1)=O.NC1SC=CN=1>C1COCC1.CO>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:30]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Nc1nccs1)N(C1CCCC1)C1CCCC1
Reactant: CC(=O)N1CCCCC1=O
Agent: NC(N)=O
Agent: NC1CCCC1
Agent: Nc1nccs1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1CCC(N(C(=O)Nc2nccs2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared according to general procedure (I). To a mixture of N-acetyl-piperidone (1.4 g) and cyclopentylamine (0.9 g) and molecular sieves (5 g) in THF (8 mL) and methanol (8 mL) was added sodium cyanoborohydride (2.1 g) and the reaction was stirred overnight at room temperature. Insoluble material was removed by filtration and after removal of solvent in vacuo the crude secondary amine (0.57 g) was isolated. The urea coupling was performed in an similar manner to the synthesis of 1,1-dicyclopentyl-3-thiazol-2-yl-urea using carbonyl imidazole and 2-aminothiazole as starting material.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:12]#[N:13])([CH:9]1[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.BrBr>O>[C:1]([N:5]=[N:6][C:7]([C:12]#[N:13])([CH:9]1[CH2:10][CH2:11]1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NNC(C)(C#N)C1CC1
Agent: BrBr
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N=NC(C)(C#N)C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a mixture of 10.0g (.055 m.) of crude 1-t-butylhydrazo-1-cyano-1-cyclopropylethane, 100 ml methylene chloride, and 50 ml water, cooled to 0°C in an ice bath, was added 8.75 g (.055 m.) of bromine dropwise over 15 minutes holding the temperature at 0° to 5°C. After the bromine addition, the reaction was stirred 10 minutes, the methylene chloride layer separated, washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off. The yield was 8.9g (90%) of a brown liquid. The liquid was chromatographed over an alumina column, eluting it with pentane, to give 8.1g of a light tan liquid which solidifies in the freezer. The infrared spectrum was consistent with the structure of the proposed compound. The product is a thermally sensitive free radical and gas generating compound. The compound has a 10 hour half-life in trichlorobenzene at 62°C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].C([O:15][C:16](=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19])C.[Al+3].[Cl-].[Cl-].[Cl-].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1.CO>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([C:1]3[NH:19][C:18]4[C:17]([C:16](=[O:15])[CH:2]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: O=c1cc(-c2ccc3c(c2)CCC3)[nH]c2ccccc12
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
To a mixture of 5-acetylindane (3.0 g, 18.7 mmol) and anthranilic acid ethyl ester (2.8 ml, 18.7 mmol) in diphenylether (47 g) was added portionwise AlCl3 (3.5 g, 26.2 mmol). The reaction mixture was stirred at 200° C. for 2.5 hours and cooled to room temperature. Hexane (100 ml) and MeOH (3 ml) were then added. The so obtained solid was filtered, washed with hexane and stirred in the presence of 5N HCl (85 ml) and acetone (10 ml). After filtration, the solid was again washed with H2O, and stirred with MeOH (15 ml) for 30 min. Filtration provided 2-indan-5-yl-1 H-quinolin-4-one (4.35 g, 89%) as a light yellow solid, MS: m/e=261 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@@H:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH3:28])=[CH:23][CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:27]([CH3:28])[C:24]2[CH:23]=[CH:22][C:21]([C@@H:17]3[O:18][CH2:19][CH2:20][NH:15][CH2:16]3)=[CH:26][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CN(c1ccc(Cl)cc1)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccc(Cl)cc1)c1ccc([C@H]2CNCCO2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
To a stirred solution of trifluoroacetic acid (51.3 μl) in water (4 ml) was added a solution of (S)-2-{4-[(4-chloro-phenyl)-methyl-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (45 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 2 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: 0% to 100% EtOAc in heptane, then 0% to 10% MeOH in EtOAc) to afford (4-chloro-phenyl)-methyl-((S)-4-morpholin-2-yl-phenyl)-amine (9 mg, 27%) as a colourless gum. MS (ISP): 305.3 ([{37Cl}M+H]+), 303.3 ([{35Cl}M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:21]>>[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:21][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=1
Reactant: CN(N)c1ccccc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and N-methyl-N-phenyl-hydrazine (CAN 618-40-6); MS (ESI) 366.2 (M+H)+.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:26])[N:11]([C:14]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[N:17]=[CH:16][N:15]=3)[NH:12][CH:13]=2)[CH:6]=[N:7][CH:8]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[ClH:1].[N:20]1([C:18]2[N:17]=[CH:16][N:15]=[C:14]([N:11]3[C:10](=[O:26])[C:9]([C:5]4[CH:4]=[C:3]([C:27]#[N:28])[CH:8]=[N:7][CH:6]=4)=[CH:13][NH:12]3)[CH:19]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CN(C)C=O
Reactant: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Product: N#Cc1cncc(-c2c[nH]n(-c3cc(N4CCOCC4)ncn3)c2=O)c1
Temperature: 25 °C

Procedure:
100 mg (0.2 mmol) of the compound from Example 43, 20 mg (0.2 mmol) of zinc cyanide and 8 mg (0.007 mmol) of tetrakis(triphenylphosphine)palladium in 2 ml DMF are reacted at 220° C. in a single-mode microwave oven (Emrys Optimizer) for a total of 105 min. After cooling to RT, the reaction mixture is concentrated under reduced pressure and the residue is taken up in formic acid and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with 0.1% formic acid added to the water). The resulting formate salt is converted into the hydrochloride by addition of 0.5 ml of a 4 N solution of hydrogen chloride in dioxane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[C:31]([CH3:35])[C:32]([Cl:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].Cl>O1CCOCC1>[ClH:34].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[C:31]([CH3:35])[C:32]([Cl:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(Cl)c(C)cc3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(Cl)c(C)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 188.1 %

Procedure:
328 mg 6-tert-butyloxy-9-[5-(5-chloro-6-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (example 134) are dissolved in 10 ml of dioxane and combined with 2.16 ml of 4N HCl in dioxane. The mixture is stirred for 16 hours at room temperature. The insoluble material is collected by filtration, washed with dioxane (10 ml), diisopropylether (10 ml) and pentane (10 ml) and dried under vacuum to yield 290 mg of 9-[5-(5-chloro-6-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride. Yield=98%. Analytical LC/MS: m/z=524 (positive ion mode [M+H]+, 1 Cl present), m/z=522 (negative ion mode [M−H]−, 1 Cl present)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[N:8][CH:9]=1)([O-])=O>CO.C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[N:8][CH:9]=1
Reactant: O=C1CCCCN1c1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCCCC2=O)nc1
Yield: 48.3 %

Procedure:
5′-Nitro-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (0.66 g, 2.98 mmol) was dissolved in 1:1 MeOH/THF (50 mL) and hydrogenated over RaNi (1 g) at 4285 psi/mole for 0.8 h. The catalyst was filtered, and the filtrate concentrated. The crude solid was purified by recrystalization from THF and hexanes to give the product as a yellow solid (0.275 g, 48% ). MS: APCI (AP+): 192.1 (M)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:12]C(O)=O.FC1C(F)=CC=C([N+]([O-])=O)C=1CC(O)=O.C(=O)([O-])[O-].[K+].[K+].FC1C(F)=CC=C([N+]([O-])=O)C=1C>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(F)c1F
Agent: Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(F)c1F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
The mixture of 2,3-difluoro-4-nitrophenylacetic acid and 2,3-difluoro-6-nitrophenylacetic acid from D16 (13.5 g) was dissolved in dimethylformamide (100 ml) and potassium carbonate (8.5 g) added. After stirring at 50° C. for 30 min the cooled solution was partitioned between aqueous hydrochloric acid and hexane. Drying (MgSO4), evaporation, and chromatography (0-5% ethyl acetate in hexane, 70 g silica column) gave 3.2 g of a 3:1 mixture of the title compound and 2,3-difluoro-6-nitrotoluene.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CC(C)=O>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][C:2]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:29][CH:28]=1
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a solution of methyl 2-hydroxy-5-(4-morpholinylcarbonyl)benzoate (may be prepared as described in Description 108, 270 mg, 1.02 mmol) in acetone (3 ml) was added cesium carbonate (663 mg, 2.04 mmol) and 4-fluorobenzyl bromide (0.16 ml, 1.32 mmol). The mixture was heated at 50° C. for 2 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (15 ml) and water (5 ml). The organic layer was dried and the solvent removed in vacuo and the residue purified by column chromatography (silicon, 4:1 ethyl acetate/cyclohexane) to give the title compound as a yellow gum. 96 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.Cl>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: CCS(=O)(=O)N1CCC(Nc2nn(COCC[Si](C)(C)C)c3c2nc(-c2c(F)cccc2F)c2cc(C=O)ccc23)CC1
Agent: Cl
Solvent: O
Product: CCS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C=O)ccc23)CC1
Temperature: 100 °C

Procedure:
A microwave tube with a maximum capacity of 20 ml is charged with 195 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde, and 10 ml of 5N aqueous HCl solution. The mixture is microwave-heated at 100° C. for 20 min and then poured into water and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and MeOH (95/5 by vol.). This gives 90 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in the form of a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.4 Hz, 3 H) 1.64 (m, 2 H) 2.10 (m, 2 H) 2.98 (m, 2H) 3.05 (q, J=7.4 Hz, 2 H) 3.62 (m, 2 H) 3.83 (m, 1 H) 6.18 (d, J=7.7 Hz, 1 H) 7.36 (t, J=7.8 Hz, 2 H) 7.71 (m, 1 H) 8.24 (broad s, 1 H) 8.34 (broad d, J=8.4 Hz, 1 H) 8.57 (d, J=8.4 Hz, 1 H) 10.11 (s, 1 H) 13.02 (s, 1 H). [M+H]+m/z=500.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCCC2)c1C
Temperature: 80 °C
Yield: 87 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(cyclohexylamino)-2-methylbenzoate (2.75 g, 8.45 mmol) in acetonitrile (25 mL), cesium carbonate (5.45 g, 16.9 mmol) and methyl iodide (6 g, 42.3 mmol) were added; resulting solution was heated at 80° C. for 20 h. On completion, the solution was cooled to room temperature and filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated and then purified by column chromatography to afford methyl 5-bromo-3-(cyclohexyl(methyl)amino)-2-methylbenzoate (2.5 g, 87%).
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:28]>C1COCC1>[ClH:28].[ClH:28].[NH2:8][CH:9]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.6 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-fluorophenyl)acetate (C50) (350 mg, 0.92 mmol) in THF (20 ml), was added 37% hydrogen chloride (1.0 ml, 12.2 mmol), and the reaction was stirred at RT for 15 hours. Then a second portion of 37% hydrogen chloride (1.0 ml, 12.2 mmol) was added again, and the reaction was further stirred at RT for 24 hours. Then the volatiles were evaporated under vacuum to obtain (R)-quinuclidin-3-yl 2-amino-2-(4-fluorophenyl)acetate dihydrochloride (325 mg; quantitative yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:28])[O:13][C:14](=[O:27])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25]Cl)[CH:17]=2)=[CH:3]1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:28])[O:13][C:14](=[O:27])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:29]=[N+:30]=[N-:31])[CH:17]=2)=[CH:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(C2=C(c3cccc(OCCCCl)c3)C(=O)OC2=O)c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)OC2=O)c2ccccc21
Temperature: 75 °C
Yield: 113 %

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-[3-(3-chloropropyloxy)phenyl]furan-2,5-dione (1.0 g, 2.2 mmol) in DMF (15 mL) was added sodium azide (0.43 g, 3 eq.) and the resulting mixture was heated at 75° C. for 24 h. The reaction mixture was cooled to room temperature and quenched with water. The product was then extracted into EtOAc. The EtOAc layer was washed with H2O, NaCl (sat.), dried over Na2SO4, and concentrated in vacuo to give 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]furan-2,5-dione (1.0 g) which was used directly in the next step without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:52]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 41.3 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0319 g, 0.0691 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2-trifluoromethylbenzenesulfonyl chloride (0.0301 mL, 0.195 mmol) to obtain 4-(2-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0191 g, yield 41%).
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(N1C(C2C=CC(C)=CC=2)=C2C(CCNC(C)C2)=N1)(C)C>>[CH:19]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH:17]([CH3:18])[NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:20])[CH3:21]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC1Cc2nn(C(C)C)c(OS(=O)(=O)C(F)(F)F)c2CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(-c2c3c(nn2C(C)C)CCNC(C)C3)cc1
Product: Cc1ccc(-c2c3c(nn2C(C)C)CC(C)NCC3)cc1
Yield: 76.1 %

Procedure:
The title compound (127 mg) was prepared as in Example 311 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and 112 mg of 4-methylphenylboronic acid. The reaction sequence also yielded 2-isopropyl-5-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. MS (ESI): exact mass calculated for C18H25N3, 283.20; found, m/z 284.5 [M+H]+. 1H NMR (600 MHz, CD3OD): 7.38-7.36 (m, 2H), 7.22-7.20 (m, 2H), 4.41 (m, 1H), 3.60-3.56 (m, 1H), 3.50-3.45 (m, 1H), 3.21-3.06 (m, 3H), 2.84-2.70 (m, 2H), 1.46 (d, J=6.6 Hz, 3H), 1.42-1.37 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=O)[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:4]2[O:19][CH2:20][CH2:21][O:22][C:3]=12>C1COCC1.[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:4]2[O:19][CH2:20][CH2:21][O:22][C:3]=12
Reactant: Nc1c(Cl)cc(C(=O)C=Cc2ccncc2)c2c1OCCO2
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(CCCc2ccncc2)c2c1OCCO2

Procedure:
A solution of 1-(4-amino-5-chloro-2,3-ethylenedioxyphenyl)-3-(pyridin-4-yl)-2-propen-1-one (1.55 g, 5 mmol) in 50 mL of THF was hydrogenated over 5% palladium on carbon (0.5 g) for approximately 2 hours. The mixture was filtered and concentrated by rotary evaporation. Purification of the residue by silica gel chromatography (2% CH3OH--CH2 +0.1% NH4OH) gave 1-(4-amino-5-chloro-2,3-ethylenedioxyphenyl)-3-(pyridin-4-yl)propan.-1-one (1.23 g, 3.8 mmol)