Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH:18]=[C:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].O1CCOC[CH2:23]1.COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:23][O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C:17]2=[CH:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])[CH:11]=1
Reactant: C1COCCO1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: COC(OC)OC
Product: COC1=CC2=CC[C@@H]3C(=CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reaction time: 48 h

Procedure:
11.5 g of 4,9(11)-androstadiene-3,17-dione [U.S. Pat. No. 3,441,559 (1969)]in 200 ml of dioxane is reacted with 20 ml of orthoformic acid trimethyl ester and 100 mg of p-toluenesulfonic acid. After 48 hours, 5 ml of pyridine is added to the solution, the latter is concentrated under vacuum, the residue taken up in ethyl acetate, washed with water, and dried over sodium sulfate. After chromatography of the crude product with a hexane-ethyl acetate gradient on silica gel containing 2% triethylamine, 9.2 g of 3-methoxy-3,5,9(11)-androstatrien-17-one is isolated; mp 153.4° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:13]1[CH2:30][CH2:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=O)=O>CN(C=O)C.O>[N:1]1([CH:13]2[CH2:30][CH2:29][C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OS(C)(=O)=O)CC2)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(n3ccnc3)CC2)CC1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
Imidazole (1.17 g, 17.3 mmol, 3.0 eq.) was added to a stirred suspension of NaH (20.16 mmol, 3.5 eq.) in DMF (10 ml) at 0° C. and the reaction mixture was allowed to stir at the same temperature for 20 min. A solution of tert-butyl 9-(methylsulfonyloxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g, 5.76 mmol, 1.0 eq.) in DMF (5 ml) was added to the reaction mixture at 0° C. and it was stirred at RT for 16 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (60 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 3% MeOH/MC) to yield the desired product as a colorless oil. Yield: 59% (1.10 g, 3.45 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][C:19]#[N:20])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2onc(-c3ccc(Cl)cc3)c2c1

Procedure:
A mixture of 5-bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole (45 g.) and sodium cyanide (7.4 g.) in dry dimethylformamide (800 ml.) was heated on a steam bath for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness, to give 3-(4-chlorophenyl)-1,2-benzisoxazol-5-ylacetonitrile (m.p. 118°C.).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9]Br>CN(C=O)C>[Br:9][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:8])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Oc1ncccc1F
Solvent: CN(C)C=O
Product: Oc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 3-fluoro-2-hydroxypyridine (1 g, 8.8 mmol) in dry DMF (11 mL) was cooled in an ice bath. Bromine (1.55 g, 9.7 mmol) was added drop-wise over a period of 10 min and the reaction mixture stirred at 0° C. for 1 h then allowed to warm to room temperature and stirred for an additional 2 h. The reaction was quenched with water. The aqueous was extracted with DCM (×4) and the combined organics dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (gradient: 20-100% EtOAc in pet. ether 40-60) yielded 5-Bromo-3-fluoro-2-hydroxypyridine as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH2:34][C:35]#[N:36]>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH2:34][C:35]#[N:36]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC1(C)OB(c2ccc(CC#N)c(F)c2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CC#N)c(F)c1
Yield: 99.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (350 mg, 1.1 mmol) was reacted with 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (440 mg, 1.7 mmol) to afford the desired product (400 mg, >99%) as a brown solid: ESI MS m/z 365 [C20H13FN2O2S+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.O.[OH-].[Cs+].Br[CH2:34][CH3:35].[ClH:36]>CN(C)C=O>[ClH:36].[ClH:36].[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:4]2[CH:5]=[N:1][N:2]([CH2:34][CH3:35])[CH:3]=2)[N:8]=1)[CH3:29]
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CCBr
Agent: Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cnn(CC)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol; prepared according to Example 21, Step A) in dry N,N-dimethyl formamide (0.5 mL) was added cesium hydroxide hydrate (8.7 mg, 0.052 mmol) and bromoethane (5.7 mg, 0.052 mmol). The mixture was stirred under a nitrogen atmosphere for 60 minutes at ambient temperature. The mixture was filtered, washed with methanol and ethyl acetate, and concentrated under a stream of nitrogen. The material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The isolated product was dissolved in a mixture of dichloromethane and methanol. Hydrogen chloride (0.5 mmol; 2M solution in diethyl ether) was added. Removal of the solvent under reduced pressure followed by high vacuum gave N-(3-ethyl-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (5.0 mg). MS (APCI), positive scan, m/z=414.2 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:44])[C:4]([NH:6][C@@H:7]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[C:32]=1[F:39])=[O:16])=[O:9])=[O:5].C([O-])(O)=O.[Na+].O.[C:51](Cl)(=[O:54])[CH:52]=[CH2:53]>C1COCC1>[ClH:38].[C:51]([NH:2][C@@H:3]([CH3:44])[C:4]([NH:6][C@@H:7]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[C:32]=1[F:39])=[O:16])=[O:9])=[O:5])(=[O:54])[CH:52]=[CH2:53]
Reactant: C=CC(=O)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)N)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3F)ncnc2cc1OC)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
The compound (30 mg, 0.046 mmol) obtained in Example 12 and NaHCO3 (11.6 mg, 0.14 mmol) were dissolved in THF (0.8 mL): H2O (0.2 mL), and acryloyl chloride (0.004 mL, 0.046 mmol) was added thereto at 0° C. The mixture was stirred at 0° C. for 30 min, and an aqueous solution of NaHCO3 was added thereto, followed by washing several times with chloroform. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the title compound (15 mg, 8%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C1C=CC=CC=1.C(OC)(C)(C)C>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:42]([C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=1)(=[O:43])=[O:44])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)CC(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (308 mg, 0.70 mmol), 4-nitrobenzenesulfonyl chloride (190 mg, 0.77 mmol), N,N-diisopropylethyl-amine (181 mg, 1.4 mmol) and DMAP (20 mg), in benzene (5 mL) was heated under reflux for 3 hours, then concentrated in vacuo and the residue dissolved in ethyl acetate, and washed with saturated NaHCO3 solution, water, and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The tan solid thus obtained was triurated in warm tert-butylmethyl ether, and filtered to give 419 mg (95%) of the title compound as a white solid, mp=121-123° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C@H:8]([NH2:17])[C@H:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:18](=O)[CH:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][N:17]1[CH:8]([CH3:7])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:16][CH:18]1[CH:19]([CH3:21])[CH3:20]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: CC(C)C=O
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)CCN1C(C)C(c2ccccc2)OC1C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 ml. of toluene, 43 g. (0.5 moles) of methyl acrylate and 76 g. (0.5 moles) of l-norephedrine are added to a 500 ml. three neck flask and stirred at room temperature for 24 hours. To the solution is added 50.4 g. (0.7 mole) of isobutyraldehyde and the mixture is heated to remove the water formed, by azeotropic distillation. When no more water can be removed, concentrate and distill. The oxazolidine propionic acid methylester boils at 140°-160° C./0.5 mm. The yield is 129 g. (87%) n23d =1.5020.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C@@H:29]5[C@@H:33]([OH:34])[CH2:32][CH2:31][NH:30]5)=O)[CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.CSC.B.B.CO>C1COCC1>[CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][CH:23]([NH:26][CH2:27][C@@H:29]5[C@@H:33]([OH:34])[CH2:32][CH2:31][NH:30]5)[CH2:24][CH2:25]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NC(=O)[C@H]5NCC[C@@H]5O)CC4)n3)ccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NC[C@H]5NCC[C@@H]5O)CC4)n3)ccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
184 mg (0.39 mmol) of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid [6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl]amide was dissolved in 5 ml of THF, and 579 μl of 2M borane dimethyl sulfide solution in THF were added at 70° C. under nitrogen atmosphere, and the mixture was subsequently stirred at 70° C. for 2 hours. 579 μl of borane/dimethyl sulfide solution was again added, and the mixture was heated in a heating block at 70° C. for a further 4 hours. In order to decompose the excess borane, 1 ml of MeOH was added dropwise. The reaction mixture was evaporated, and 1 ml of water and 1 ml of conc HCl were added to the oily residue. The mixture was stirred at room temperature for 2 h, rendered alkaline using 2 molar NaOH and extracted with ethyl acetate. The organic phase was dried and purified by column chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][NH:36][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:37][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: CC(C)(C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 78.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.7 mmol) with 4-(tert-butyl)benzyl amine (375 μL, 2.1 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) followed by SCX chromatography to give 6-(4-tert-butylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (240 mg, 78%). MS (ES+) m/z: 439 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[N:10]([CH:11]2[CH2:17][CH:16]3[N:18]([CH2:19][CH2:20][C:21]4([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=2[N:7]=1.[CH2:37]([N:39](CC)[CH2:40]C)C>C(Cl)Cl>[CH3:37][N:39]([CH3:40])[C:1]([N:24]1[CH2:23][CH2:22][C:21]([CH2:20][CH2:19][N:18]2[CH:16]3[CH2:15][CH2:14][CH:13]2[CH2:12][CH:11]([N:10]2[C:9]4[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=4[N:7]=[C:6]2[CH3:5])[CH2:17]3)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)N(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., to a stirred solution of phosgen (0.25 mL, 2.0 in toluene) was added a solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1H-benzimidazole (71 mg, 0.17 mmol) in methylene chloride and triethylamine (excess). The mixture was stirred for 30 minutes at 0° C. and further one hour at room temperature. Nitrogene gas was then introduced to remove the excess phosgen. To this mixture was added excess dimethylamine and the resulting mixture was stirred overnight at ambient temperature. After being diluted with methylene chloride, the organic phase was washed with brine, dried over anhydrous sodium sulfate and purified by flash chromatography. N,N-dimethyl-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxamid was obtained as foam (52 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=7.3 Hz, 1H), 7.37-7.34 (m, 2H), 7.31-7.29 (m, 3H), 7.23-7.12 (m, 3H), 4.61 (br, 1H), 3.44-3.38 (m, 2H), 3.25 (br, 2H), 3.12-3.06 (m, 2H), 2.80 (s, 6H), 2.58 (s, 3H), 2.38-2.36 (m, 2H), 2.19-2.15 (m, 2H), 1.93-1.81 (m, 10H), 1.61 (d, J=7.3 Hz, 2H). HRMS m/z (M+H)+ calcd: 500.3389, obsd: 500.3386.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[C:27](O)(=[O:29])[CH3:28]>C(Cl)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:27](=[O:29])[CH3:28])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:24])([F:26])[F:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Solvent: CC(=O)Cl
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C)cc2)cc1

Procedure:
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (0.60 g, 1.57 mmol) was heated in 2 mL acetyl chloride and 2 mL acetic acid at reflux for 2 h. An additional 2 mL acetyl chloride was added and the mixture was heated to reflux for an additional 5 h. The mixture was cooled and concentrated. Recrystallization from ether/hexane furnished the product as a white solid: Anal. Calc'd for C19H16N3O3SF3 : C, 53.90; H, 3.81; N, 9.92; S, 7.57. Found: C, 54.04; H, 3.80; N, 9.93; S, 7.66.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[O:11][CH:12]1[CH2:16][CH2:15][CH2:14]O1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:14]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:16][CH2:12][OH:11])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC1CCCO1
Product: OCCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12

Procedure:
The compound was prepared in the same way as described in example 2/4, starting from indole and 2-methoxy-tetrahydrofuran.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([C:8]([CH3:10])=O)([CH3:7])=O>>[CH3:7][C:5]12[NH:4][CH2:1][CH2:2][NH:3][C:8]1([CH3:10])[NH:3][CH2:2][CH2:1][NH:4]2
Reactant: NCCN
Reactant: CC(=O)C(C)=O
Product: CC12NCCNC1(C)NCCN2
Yield: 37 %

Procedure:
The compound was prepared in 37% yield by reacting ethylenediamine with biacetyl according to the method of Stetter, Chem. Ber. 86, 69 (1953).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccc2c(c1)cc(-c1cc(OC)c(O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 42.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.415 g, 0.985 mmol) was dissolved in acetonitrile (16.0 mL), and the solution was treated with diethylamine (2.04 mL, 19.7 mmol), acetic acid (1.10 mL, 19.7 mmol) and sodium triacetoxyborohydride (0.626 g, 2.96 mmol) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(diethylaminomethyl)indol-2-yl]isoindolinone (0.202 g, 43%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1.CO>[S:17]([C:6]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([NH:7][CH2:8][CH2:9][OH:10])[C:5]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[NH:4][CH2:3][CH2:2][OH:1])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: OCCNCCNCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(NCCO)(C(NCCO)(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N′-bis(2-hydroxyethyl)-ethylenediamine (Aldrich, 14.8 g, 100 mmol) and pyridine (Fluka, 200 mL) was stirred at 0° C. under nitrogen while a solution of toluene-4-sulfonyl chloride (Fluka, 77 g, 400 mmol) dissolved in pyridine (Fluka, 100 mL) was dropped into the solution over a period of 75 minutes. The temperature was slowly raised to room temperature and continued stiffed for 4 hours. Solution was poured into a mixture of ice (250 mL) and hydrochloric acid (concentrated, 250 mL) while stirring to afford a dark sticky oil. Solvents were removed by decantation, product crude washed with water, decanted and re-dissolved in methanol (250 mL). The resulting slurry was isolated by filtration and the crude product was re-dissolved in hot methanol (60° C., 600 mL) and cooled down. Solid product was filtered off and dried in vacuo. Yield 36.36 g (47.5%). Product was verified by NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>CO>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([NH2:37])=[O:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-[2-((3S,5S)-1-tert-butoxycarbonyl-5-hydroxymethyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[N:29]=1.C(N(CC)CC)C>C(#N)C>[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][N:40]([CH2:6][CH2:7][O:8][C:9]4[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=4)[CH:15]=[O:16])[CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[N:29]=1
Reactant: CS(=O)(=O)OCCOc1cccc(C=O)c1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cccc(C=O)c4)CC3)C2)cs1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2-(3-Formylphenoxy)ethyl methanesulfonate (example 10, step a) (0.38 g) was added to a solution of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.62 g) and triethylamine (0.55 mL) in acetonitrile (5 mL) and the resulting mixture stirred for 16 h at 65° C. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was separated and extracted with ethyl acetate (2×25 mL). The organic phases were combined, washed with brine (25 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 47.5:47:5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient to give the subtitled compound as a yellow oil. Yield 0.48 g.