Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.[CH3:8][C:9]([CH3:14])([CH3:13])[CH2:10][CH:11]=O.[S-:15][C:16]#[N:17].[K+].II>C(#N)C>[C:9]([C:10]1[S:15][C:16](=[NH:17])[N:1]([CH2:2][C:3]2([OH:7])[CH2:6][CH2:5][CH2:4]2)[CH:11]=1)([CH3:14])([CH3:13])[CH3:8]
Reactant: CC(C)(C)CC=O
Reactant: NCC1(O)CCC1
Reactant: N#C[S-]
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cn(CC2(O)CCC2)c(=N)s1
Yield: 32.4 %

Procedure:
A mixture of 1-(aminomethyl)cyclobutanol (prepared from cyclobutanone as described in WO 2006/100208) (7.2 g, 71 mmol), 3,3-dimethylbutanal (9.8 mL, 78 mmol), 4 Å molecular sieves (10 g, 8-12 mesh beads), potassium thiocyanate (9.2 g, 95 mmol) and iodine (18 g, 71 mmol) in acetonitrile (100 mL) were processed as described in Example 18A to provide the title compound (5.5 g, 23 mmol, 32% yield). MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([CH:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:17]3)[NH:11][NH:10][C:9]1=[O:34])(OCC)=O>O.C(O)C>[C:30]1([CH3:33])[CH:31]=[CH:32][C:27]([S:24]([NH:23][CH:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[C:14]([C:12]4[CH2:13][CH2:8][C:9](=[O:34])[NH:10][N:11]=4)[CH:15]=3)[CH2:19]2)(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1C=C(c2ccc3c(c2)CC(NS(=O)(=O)c2ccc(C)cc2)C3)NNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C4=NNC(=O)CC4)cc3C2)cc1

Procedure:
600 mg (15 mmol) of sodium hydroxide in 2 ml of water are added to 2.3 g (5 mmol) of 4-carbethoxy-6-(2-p-toluenesulfonamido-indan-5-yl)-dihydro-pyridazin-3(2H)-one in 40 ml of ethanol, and the mixture is stirred over night in order to achieve hydrolysis. The reaction product which is precipitated on acidifying is filtered off with suction and heated in glacial acetic acid for 10 minutes at the boil. The desired compound crystallises out on cooling.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:43])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:43][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[S:11]([N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH2:10][CH2:9]1)(=[O:12])=[O:13]
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(N1CCN(S(=O)(=O)c2cc(F)ccc2CBr)CC1)C(F)(F)F
Yield: 48.9 %

Procedure:
To a solution of Intermediate 2 (9.5 g, 27 mmol) in CCl4 (70 mL) was added AIBN (0.5 g, 3 mmol) and the mixture was brought to reflux. NBS (5.3 g, 30 mmol) was added and the mixture was refluxed for 4 h, cooled and filtered to remove solids. Concentration and purification by flash chromatography (0% to 25% EtOAc/hexane) gave the title compound as colorless oil (5.715 g, 49% yield). 1H NMR (300 MHz, CDCl3) δ: 7.65-7.60 (2H, m), 7.33-7.27 (1H, m), 4.83 (2H, s), 3.82-3.79 (2H, m), 3.74-3.71 (2H, m), 3.34-3.30 (4H, m). LCMS (M+H) calcd for C13H14BrF4N2O3S: 433.97; found: 435.11.
Reaction SMILES: N[C@@:2]12[N:9]([CH3:10])[C@@H:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[CH3:11]OC1CCC(OC)O1.[CH2:20]([C:27](O)=O)[C:21]([CH2:23][C:24](O)=[O:25])=O>>[CH2:2]([N:9]1[CH:10]2[CH2:27][CH2:20][CH:21]1[CH2:23][C:24](=[O:25])[CH2:11]2)[C:8]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1[C@@H]2CCC[C@@]1(N)CC2
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: COC1CCC(OC)O1
Product: O=C1CC2CCC(C1)N2Cc1ccccc1

Procedure:
For example, the protected aminotropane intermediate 16 can be prepared by reacting 2,5-dimethoxy tetrahydrofuran 17 with 1,3-acetonedicarboxylic acid 18 to provide 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 19, commonly N-benzyltropanone. N-benzyltropanone is then reacted with a slight excess of di-tert-butyl dicarbonate in the presence of a transition metal catalyst to provide the protected Boc intermediate 20, which is reduced to provide the protected aminotropane intermediate 16.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].C(=O)([O-])O.[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>CO>[CH3:2][O:3][C:4]([CH:5]1[CH2:7][S:8][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:6]1)=[O:9]
Reactant: COC(=O)[C@@H](N)CS
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CSC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 76.3 %

Procedure:
1.72 g of L-cysteine methylester hydrochloride was neutralized by addition of 0.84 g of sodium hydrogen carbonate. The resulting ester was dissolved in 2 ml of methanol, and to this solution was added a solution of 0.94 g of benzaldehyde in 3 ml of methanol. The mixture was then stirred at room temperature for 40 hours under a nitrogen atmosphere. Ether was added to the reaction mixture, and then the mixture was extracted with diluted hydrochloric acid. The extract was neutralized by addition of sodium hydrogen carbonate and then extracted with ether. The organic portion was dried over anhydrous sodium sulfate and placed under reduced pressure for distilling off the solvent. There was obtained 1.51 g of 4-methoxycarbonyl-2-phenylthiazolidine as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].[K+].C(O)(=O)C.[NH:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[NH:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]([OH:19])[C:1]#[N:2])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: O=Cc1cccc(Nc2ccccc2)c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC(O)c1cccc(Nc2ccccc2)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
1.5 g of KCN and 1.8 ml of acetic acid were added to 2.5 g of the aldehyde thus obtained dissolved 40 ml of ethanol and then left overnight under stirring. Then, the reaction mixture was poured into 100 ml of 2N-HCl and the extraction was effected with benzene. After washing with NaCl aqueous solution, the benzene layer was condensed to yield 2.7 g of 3-anilino-α-cyanobenzylalcohol.
Reaction SMILES: COC(=O)[NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([N:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=3[C:14]3=[N:22][O:23][C:24]([CH3:25])=[C:13]3[C:12]2=[O:26])[CH2:6]1.C[Si]([I:32])(C)C.CO>ClCCl>[IH:32].[NH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([N:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=3[C:14]3=[N:22][O:23][C:24]([CH3:25])=[C:13]3[C:12]2=[O:26])[CH2:6]1
Reactant: C[Si](C)(C)I
Reactant: COC(=O)NC1CCCC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Solvent: ClCCl
Solvent: CO
Product: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Product: I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]carbamic acid methyl ester, 2.0 g (5.1 mmol) in 50 mL of dichloromethane was added 1.74 mL (12.2 mmol) of trimethylsilyliodide. The reaction mixture was stirred overnight at ambient temperature and was quenched dropwise with 3.0 mL (73.4 mmol) of methanol. The mixture was stirred 30 minutes at ambient temperature and was concentrated to dryness. The residue was triturated with ether, filtered and dried to provide a quantitative yield of the desired isomer as a tan solid. 1H—NMR is consistent with structure. MS (ion spray) 332.1 (M+ for free base).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]([N:9]=[N:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]>>[CH:6]([N:9]=[N:10][C:11]1([C:17](=[O:2])[NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CC(C)N=NC1(C#N)CCCCC1
Product: CC(C)N=NC1(C(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 100 ml of 96% sulfuric acid cooled to 0° C. in an ice bath was added 13.5 grams (0.0755 moles) of 1-isopropylazo-1-cyanocyclohexane (from Example 4-b-6) dropwise over 1/2 hour while holding the temperature at 0° C. After the addition was complete the temperature was allowed to rise to 10° C. over 1/2 hour and to 25° C. over another 1/2 hour and then stirred another 1/2 hour at 25° C. The reaction mixture was poured onto 1/2 liter of ice and stirred until all of the ice dissolved. A white solid that formed was filtered off and the aqueous acid filtrate was extracted with 200 ml of methylene chloride. The methylene chloride extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure on a rotating evaporator. The product was a light brown liquid and weighed 5.0 grams (33.7% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-carbamylcyclohexane (strong broad carbonyl band at 1675-1750 cm-1 and NH band at 3500 cm-1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]([CH2:18][CH2:19][OH:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[O:11]([CH2:18][CH:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCOc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
At −78° C., a solution of dimethylsulphoxide (5.11 ml, 72 mmol) in DCM (50 ml) was added dropwise to a solution of oxalyl chloride (6.12 ml, 72 mmol) in DCM (150 ml). The reaction mixture was stirred for 10 min at −78° C. A solution of 2-phenoxyethanol (10.0 g, 72 mmol) in DCM (70 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 10 min. A solution of triethylamine (50 ml, 360 mmol) in DCM (50 ml) was added dropwise. The reaction mixture was stirred for 10 min at −78° C. It was warmed to room temperature. The reaction mixture was washed with a 10% aqueous solution of sodium hydrogensulphate (2×200 ml) and subsequently with brine (2×200 ml). It was dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane (1:3) as eluent, to give 2.73 g of phenoxyacetaldehyde.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CC1C[CH:16]([O:32][CH:33]([CH2:49][CH:50]1OC1)CCCCCCCCCCCCCCC)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CC(C)=[O:56]>>[OH:56][CH:49]([CH2:33][O:32][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:50][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCCCCCC(CC1CO1)OC(CCCCCCCCCCCCCCC)CC1CO1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCC(c2ccccc2)CC1
Temperature: 180 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-Phenylpiperidine (1.8 g, 0.011 mol) and 2,3-epoxypropyl-n-hexadecylether (2.98 g, 0.01 mol) were combined and heated to 180° C. for 30 minutes. The reaction mixture was cooled, acetone was added, and the mixture was stirred for 16 hours. The resulting solids were collected and recrystallized from hot acetone to give pure product (2.3 g, 50% yield): mp 64°-65° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1>>[ClH:16].[CH3:26][O:25][C:19]1[CH:20]=[C:21]([O:23][CH3:24])[N:22]=[C:17]([NH:15][CH:9]2[C:10]3[NH:11][C:12]4[C:4](=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=4)[C:5]=3[CH2:6][CH2:7][CH2:8]2)[N:18]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N
Product: COc1cc(OC)nc(NC2CCCc3c2[nH]c2ccc(C)cc32)n1
Product: Cl

Procedure:
N-(4,6-Dimethoxypyrimidin-2-yl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride was prepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-chloro-4,6-dimethoxypyrimidine in a similar manner as described in Example 22 to give 12 mg (8%) of a redish solid. 1H-NMR (CDCl3): δ 10.4 (s, 1H), 7.40 (s, 1H), 7.13 (m, 2H), 6.82 (s, 1H), 5.46 (d, 1H), 5.30 (s, 1H), 4.08 (s, 6H), 2.65 (m, 2H), 2.33 (s, 3H), 2.06 (m, 2H), 1.80 (m, 2H); MS m/z 339 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH3:7][O:8][C:9]1[C:10]([OH:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[OH-].[K+]>O1CCCC1.O>[CH3:1][N:2]([CH3:6])[C:3]([O:17][C:10]1[C:9]([O:8][CH3:7])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])=[S:4]
Reactant: COc1cccc(C=O)c1O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C=O)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
A solution of N,N-dimethylthiocarbamoyl chloride (10 g) in tetrahydrofuran (40 ml) was added dropwise at <12° C. over 30 minutes to a stirred solution of 3-methoxy-2-hydroxybenzaldehyde (12.3 g) and potassium hydroxide (4.6 g) in water (105 ml) then the mixture was stirred at ambient temperature for 15 minutes. 10% Aqueous potassium hydroxide solution (30 ml) was added, then the product was extracted into toluene (3×150 ml). The combined extracts were washed with water (150 ml) then dried (MgSO4). The solvents were removed in vacuo and the residue was crystallised from methanol to give 2-(N,N-dimethylthiocarbamoyloxy)-3-methoxybenzaldehyde (10.5 g) as a yellow solid which was used without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([NH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl>[CH2:5]([NH:17][C:28](=[O:29])[CH2:27][CH2:26][CH:25]([OH:30])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCC1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)CCC(O)CCCCCCC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 19.0 g aluminum chloride, dissolved in methylene chloride, was cooled to 0° C. and 46.5 g dodecylamine in methylene chloride was added dropwise (exothermic). At room temperature, 19.3 g gamma-undecalactone was added rapidly. The temperature rose to 36° C. The reaction was stirred at room temperature for 4 hours. The mixture was quenched with water and filtered over Celite. The liquid was extracted with ether and washed with water and brine. The solution was dried, filtered and evaporated to dryness. The resulting brown crystals were purified by recrystallization from ether/ethylacetate to give pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH3:20])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:38])[CH:31]2[Si:34](Cl)([CH3:36])[CH3:35])=[C:27]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=2)[C:26]=1[O:49][CH3:50])([CH3:24])([CH3:23])[CH3:22].O>CCOCC.C([Cu])#N>[C:21]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([CH3:38])[CH:31]2[Si:34]([CH:16]2[C:15]3[C:19](=[C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=4)[CH:12]=[CH:13][CH:14]=3)[CH:18]=[C:17]2[CH3:20])([CH3:36])[CH3:35])=[C:27]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=2)[C:26]=1[O:49][CH3:50])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1=Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)Cl
Agent: N#C[Cu]
Solvent: CCOCC
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 7.88 g (30.0 mmol) of 7-(4-tert-butylphenyl)-2-methyl-1H-indene in 200 ml of ether 12.0 ml (30.0 mmol) of 2.5 MnBuLi in hexanes was added in one portion at −40° C. This mixture was stirred overnight at room temperature, then cooled to −40° C., and 215 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −40° C., and a solution 13.2 g (30.0 mmol) of [6-tert-butyl-4-(4-tert-butylphenyl)-5-methoxy-2-methyl-1H-inden-1-yl](chloro)dimethylsilane (prepared as described above) in 150 ml of ether was added in one portion. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water were added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by 2×75 ml of dichloromethane. The combined organic elute was evaporated to dryness, and the residue was dried in vacuum. This procedure gave 20.1 g of the title product (on the evidence of NMR spectroscopy, it has ca. 90% purity and is a ca. 1:1 mixture of the distereomers) as yellowish glass which was further used without an additional purification.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][S:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH2:30])(=[O:13])=[O:12]>C(#N)C>[ClH:9].[CH3:10][S:11]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH:30][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: CCCCCCC(=O)Cl
Solvent: CC#N
Product: CCCCCCC(=O)Nc1cnc2ccccc2c1NCCOCCS(C)(=O)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Heptanoyl chloride (1 mL, 6.5 mmol) was added dropwise to a solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (prepared as described in Parts A-E of Example 1, approximately 1.8 g, approximately 5.9 mmol) in acetonitrile (30 mL). The reaction mixture was allowed to stir for 1 hour at room temperature, then was concentrated under reduced pressure to yield N-[4-({2-[2-(methylsulfonyl)ethoxy]ethyl}amino)quinoline-3-yl]heptanamide hydrochloride as an orange foam that was used without purification.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)#[N:2]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: COc1ccc(CN=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.8 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-methoxybenzylamine (0.40 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.50 g, 2.1 mmol, yield: 80%) as colorless powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:5]1)(=O)C.[NH3:30]>CO>[C:19]([CH2:18][CH2:17][CH2:16][NH:15][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:14])(=[O:21])[NH2:30]
Reactant: N
Reactant: COC(=O)CCCNC(=O)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C(C)=O
Solvent: CO
Product: NC(=O)CCCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Yield: 43 %

Procedure:
A sealed glass bomb containing methyl 4-{[1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-yl]carbonylamino}butanoate (95 mg, 0.239 mmol) in methanol with saturated ammonia (7 mL) was heated to 80° C. for 18 hours. The reaction mixture was condensed and he resulting solid was purified by HPLC to afford the title compound (35 mg, 43% yield). 1H NMR (DMSO-d6) δ 13.43 (br s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.87 (d, 1H), 7.58 (d, 1H), 7.37 (t, 1H), 7.29 (s, 1H), 6.75 (br s, 1H), 3.75 (m, 2H), 2.09 (t, 2H), 1.73 (t, 2H); ES-MS (m/z) 341[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C1COCC1>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1cc(I)ccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(I)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 2-amino-5-iodobenzamide (15.8 g, 60.3 mmol) and triethylamine (7.32 g, 72.4 mmol) in THF (300 mL) was added dropwise ethyl chloroglyoxylate (9.05 g, 66.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the precipitated insoluble material was collected by filtration. The solid was washed with water to give ethyl ((2-(aminocarbonyl)-4-iodophenyl)amino)(oxo)acetate as a white powder (20.9 g, 96%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]3[N:14]=[CH:15][NH:16][C:10]=3[CH2:9]2)[C:5]([N:17]([CH3:19])[CH3:18])=[CH:4][N:3]=1.O.Cl.[CH3:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:24]>O1CCOCC1.CN(C=O)C>[CH3:24][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][C:11]4[N:14]=[CH:15][NH:16][C:10]=4[CH2:9]3)[C:5]([N:17]([CH3:19])[CH3:18])=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:22]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CN(C)c1cnc(Cl)nc1N1CCc2nc[nH]c2C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CN(C)Cc1ccc(Nc2ncc(N(C)C)c(N3CCc4nc[nH]c4C3)n2)cc1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
50 mg 2-chloro-4-(3,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-5-dimethylamino-pyrimidine are suspended in 60 μL of 1,4-dioxane, 20 μL water and 90 μL of a 5 M hydrochloric acid (in 1,4-dioxane) and mixed with 55 mg 4-dimethylaminomethyl-phenylamine. This mixture is heated to 95° C. and stirred for 20 h at this temperature. The suspension obtained is diluted with DMF and then purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 95% water (10 mM ammonium hydrogen carbonate and 38 mM ammonia) and 5% acetonitrile and at the finishing point of 50% water and 50% acetonitrile. The fractions are freeze-dried. The residue is taken up in acetonitrile, combined with aqueous hydrochloric acid and freeze-dried once more.