Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].[H-].[Na+].C(OCC)=O>O>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: O
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
In a flask similar to that employed in Example 1 were placed under argon atmosphere 1.96 g (6.73 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 10 mL of acetonitrile and 0.434 g (10.9 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture was added 0.85 mL (10.5 mmol) of ethyl formate, and the mixture was stirred for 4 hours at the same temperature. Subsequently, to the mixture was slowly added 10 mL of chilled water. The mixture was then extracted with 30 mL of ethyl acetate which was previously chilled in an ice bath. The organic portion was dried over anhydrous magnesium sulfate, and filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.74 g (yield: 82%) of 3-[2-cyclo-propyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([SH:6])[CH3:5].Cl[CH2:8][C:9]1[CH:26]=[CH:25][C:12]2[N:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][C:11]=2[CH:10]=1.O>CN(C)C=O>[CH:22]1([CH2:21][N:13]2[C:12]3[CH:25]=[CH:26][C:9]([CH2:8][S:6][CH:4]([CH3:5])[CH3:3])=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:23][CH2:24]1
Reactant: CC(C)S
Reactant: CC(C)(C)Cc1nc2cc(CCl)ccc2n1CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)SCc1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of sodium hydride (washed with hexane, 30 mg, 1.3 mmol) in N,N-dimethylformamide (2 mL) was added 2-propanethiol (117 μL, 1.3 mmol) at 0° C. After stirring for 30 min, a N,N-dimethylformamide solution of 5-(chloromethyl)-1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole (Step E) was added and the mixture was stirred at 100° C. for 17.5 h. Water (5 mL) was added and the mixture was extracted with ethyl acetate (15 mL×2) and washed with brine (5 mL). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by pTLC (hexane:ethyl acetate=3:1) to give the title compound (74 mg, 67% over 2 steps) as pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.C[O-].[Na+].CO.O[Li].O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC1c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: O=C(O)C1CC1c1ccc(Cl)cc1
Yield: 98.5 %

Procedure:
Ethyl 2-(4-chlorophenyl)-cyclopropanecarboxylate (0.210 g, 0.935 mmol) was placed in a 50 ml flask and dissolved in EtOH (5 ml). NaOMe in MeOH (25%, 0.808 g, 3.74 mmol) was added to the mixture. The mixture was heated for 17 hours under reflux and then concentrated. The residue was dissolved in MeOH (10 ml), and 1M solution of LiOH—H2O (3.74 ml, 3.74 mmol) was added. The methanol was removed under reduced pressure. The residue was diluted with water (10 ml) and washed with EtOAc (10 ml). The aqueous layer was acidified by 1N HCl (10 ml) to pH 1 and a solid precipitated out of solution. The mixture was extracted with EtOAc (3×10 ml) and the combined extracts were dried over MgSO4, filtered, and concentrated to provide 181 mg of the title compound as a solid (98%). The crude solid was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].C([CH:13](S)[C:14]([O-])=[O:15])C.[CH3:18][OH:19]>>[NH2:8][C:7]1[C:6]([C:9]#[N:10])=[C:3]([S:4][CH3:5])[S:2][C:1]=1[C:18]([O:15][CH2:14][CH3:13])=[O:19]
Reactant: CCC(S)C(=O)[O-]
Reactant: CO
Reactant: CSC(SC)=C(C#N)C#N
Product: CCOC(=O)c1sc(SC)c(C#N)c1N
Yield: 99 %

Procedure:
A mixture of [bis(methylsulfanyl)methylene]malononitrile (40 g, 230 mmol), ethylthioglycolate (29 g, 230 mmol) and TEA (24 mL, 173 mmol) in MeOH (600 mL) was allowed to stir at reflux for 2 h. The reaction mixture was allowed to cool overnight and the precipitate was filtered off, washed with cold MeOH (3×50 mL) to give ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (52.4 g, 99%). LCMS: (FA) ES+ 275.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH2:4].[CH3:5]/C=C/C.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=C1>CCCCCCC>[CH3:4][C:3]([CH2:2][CH:1]1[C:9](=[O:15])[O:14][C:12](=[O:13])[CH2:11]1)=[CH2:5]
Reactant: O=C1C=CC(=O)O1
Reactant: C/C=C/C
Reactant: C=CCC
Solvent: CCCCCCC
Product: C=C(C)CC1CC(=O)OC1=O
Temperature: 80 °C

Procedure:
A mixture of 92.0 g (0.1 mole) of polyisobutene (Indopol H-100 ac. m. wt. 920) and 19.6 g. (0.2 mole) of maleic anhydride is heated at 205°-210° C. for 24 hours. During the first 2 hours of heating, the temperature remains at about 205° C., thereafter the heating range is 205°-210° C. The reaction mixture is allowed to cool to about 80° C. before the addition of 150 ml. of heptane and, after stirring well, is filtered. The filtrate is stripped at about 55° C. and 10 mm. pressure and finally at 150°-170° C. for about one hour to remove any trace of unreacted maleic anhydride. Weight of the dark, reddish, viscous reaction product is 93.6 g. In addition, 11.2 g. of unreacted maleic anhydride is recovered.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH2:46][CH2:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH2:46][CH2:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCC[C@H]2CCCCN2C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,10aR)-6-oxodecahydropyrido[1,2-a]azepin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 54 (4.7 mg, 0.021 mmol) to give a white solid (12 mg, 91% yield). Anal. Calcd. for C41H54N4O6S m/z 730.4. found: 731.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.07 (12H, m), 5.33 (1H, t, J=4.7 Hz), 5.15-5.08 (1H, m), 5.05-4.95 (1H, m), 4.83-4.72 (1H, m), 4.15 (1H, d, J=11.5 Hz), 3.88-3.77 (1H, m), 3.68 (3H, s), 3.15 (1H, ddd, J=14.2, 11.1, 2.7 Hz), 2.90-2.68 (6H, m), 2.51-2.35 (3H, m), 2.08-1.99 (2H, m), 1.85-1.42 (20H, m), 1.06-0.90 (1H, m).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[CH:23]1([CH:22]=[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:35])[CH3:36])=[CH:30][CH:29]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(C(C)(C)O)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(C)(C)O)cc3)cc2c1
Yield: 85.7 %

Procedure:
A mixture of 2-{4-[1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (160 mg, 0.31 mmol) in ethanol (3 mL) and an aqueous sodium hydroxide solution (10%, 1.5 mL) was heated at reflux for 5 h. The mixture was acidified to pH 4-5 with a 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 2-{4-[2-cyclopentyl-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (100 mg, 86.2%) as a light yellow solid: LC/MS m/e calcd for C24H28N2O2 [M+H]+ 377.5, observed 377.2.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:27][C:28]([OH:30])=O)[C:13]([NH:15][CH:16]([C:23]([O:25][CH3:26])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].S(Cl)([Cl:33])=O>CO>[ClH:33].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:27][C:28](=[O:30])[N:15]([CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]([O:25][CH3:26])=[O:24])[C:13]1=[O:14]
Reactant: COC(=O)C(NC(=O)N(CCCN)CC(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCN)C1=O
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2.9 g (9 mmol) of (1-(3-aminopropyl)-3-(methoxycarbonylphenylmethyl)ureido)acetic acid trifluoroacetate are dissolved in 50 ml of methanol. After cooling down to 0° C., 1.34 g (11 mmol) of thionyl chloride are slowly added dropwise. The mixture is allowed to warm up to room temperature, then stirred overnight, concentrated and crystallized by adding ethyl acetate and methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.40 g), 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine (0.38 g), 2 M aqueous Na2CO3 solution (1.3 mL), and 1,4-dioxane (8 mL) is sparged with argon for 5 min. Tetrakis(triphenylphosphine)palladium(0) (0.10 g) is added and the mixture is stirred in a microwave oven at 170° C. for 1 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:7→0:1) to give the title compound. Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:37][C:38]1[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=2)=[CH:4][CH:3]=1
Reactant: Cn1ccnc1CCl
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4nccn4C)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.9 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was stirred for 30 min. 2-(Chloromethyl)-1-methyl-1H-imidazole (23.7 mg, 181 μmol) was added and the mixture warmed to room temperature. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 24 g Analogix column, dichloromethane) to give 2-(6-chloro-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (106 mg) as a yellow solid. MS (M+H)+=579.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(=O)C>C(#N)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:1][C:3]2[CH:7]=[CH:6][N:5]([C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cccnc1-n1ccc(C=O)n1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 2-(3-formyl-1H-pyrazol-1-yl)nicotinate (400 mg, 1.631 mmol) and morpholine (220 μl, 2.53 mmol) in acetonitrile (25 mL) NaCNBH4 (130 mg, 2.069 mmol) was added, and the pH adjusted to 5-6 by adding glacial acetic acid (110 μL, 1.922 mmol). The mixture was stirred at room temperature for 1 h, another portion of NaCNBH4 (30 mg, 0.477 mmol) added and stirred for 2 hrs. For work up the mixture was concentrated, dissolved in 100 mL of dichloromethane, washed subsequently with water and brine, dried (MgSO4), filtered off and concentrated to give 710 mg of the crude title product. Purification by chromatography over silica gel (CH2Cl2/3%-5% methanol) and concentration yielded 518 mg of the title compound as clear oil; ESI-MS [M+H]+: 317.20.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:15]=23)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(-c2ccnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c4) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][C:24]#[N:25])[CH:18]=[CH:19][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]([CH2:22][CH2:23][C:24]#[N:25])[C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:18]=[CH:19][CH:20]=1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: N#CCCNc1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(CC(=O)N(CCC#N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl(methyl)amino)acetic acid (1.05 g, 0.0056 mol) in CH2Cl2 at 0° C. under argon atmosphere was added DMAP (0.021 g), 3-(3-chlorophenylamino)propanenitrile (1 g, 0.0056 mol) and DCC (1.27 g, 0.0061 mol). The reaction mixture was allowed to stir at room temperature for 24 h. The resulting suspension was filtered, the filtrate concentrated under reduced pressure and the crude residue was subjected to silica gel chromatography to give the tert-butyl 2-((3-chlorophenyl)(2-cyanoethyl)amino)-2-oxoethyl(methyl)carbamate (1.2 g, 80%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.7 (m, 2H), 2.85 (m, 2H), 3.6-3.75 (m, 2H), 3.9 (m, 2H), 7.1-7.3 (m, 2H), 7.4 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[O:5][C:6]=1[CH3:7].[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23]CCCCC)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]>>[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23][CH2:8][C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH:3]=2)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: Cc1cc(C=O)oc1C
Product: COC(=O)c1cccc(NCc2cc(C)c(C)o2)c1C(=O)OC
Yield: 75 %

Procedure:
4,5-Dimethyl-furan-2-carbaldehyde (0.98 ml, 8 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 10% ethyl acetate/hexanes) to give 0.95 g (75%) of product as a yellow oil: 1H NMR (CDCl3) δ 7.32 (t, J=8.2 Hz, 1H), 6.97 (bs, 1H), 6.88-6.83 (m, 2H), 5.99 (s, 1H), 4.28 (d, J=5.5 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.17 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[C:32]2C=CC=CC=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[CH3:32])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To flame-dried flask under N2 was charged 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 mL of dry THF. The solution was cooled to −78° C. and 1.63 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium in hexanes added. The resulting mixture was brought to 0° C. and stirred for 10 minutes. After cooling the mixture again to −78° C., a solution of 1.0 g (3.40 mmol) of crude product from Method C in 10 mL of dry THF was added over a 10 minute period. The resulting mixture was stirred for 1 hour, at which time, 0.28 mL (4.50 mmol) of iodomethane were added. The reaction mixture was stirred for 2 hours, quenched with a saturated solution of NH4Cl and warmed to room temperature. The mixture was stirred for 5 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (M+2).
Reaction SMILES: BrC1C2C(S([Cl:15])(=O)=O)=CC=CC=2C=NC=1.C(OC(N[C@H]1CCNC1)=O)(C)(C)C.C(OC([NH:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[S:44]([C:47]1[C:48]2[C:49]([Cl:57])=[CH:50][N:51]=[CH:52][C:53]=2[CH:54]=[CH:55][CH:56]=1)(=[O:46])=[O:45])=O)(C)(C)C>>[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[S:44]([C:47]1[C:48]2[C:49]([Cl:57])=[CH:50][N:51]=[CH:52][C:53]=2[CH:54]=[CH:55][CH:56]=1)(=[O:46])=[O:45].[ClH:15]
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1S(=O)(=O)c1cccc2cncc(Cl)c12
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: Cl
Product: NCC1CCCCN1S(=O)(=O)c1cccc2cncc(Cl)c12

Procedure:
4-Chloro-5-isoquinolinesulfonyl chloride obtained in Reference Example 7 and 2-(tert-butoxycarbonylaminomethyl)piperidine (Aldrich) were used in the method of Example 1-1, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-(tert-butoxycarbonylamino)pyrrolidine, respectively, to prepare 2-[(tert-butoxycarbonylamino) methyl]-1-(4-chloro-5-isoquinolinesulfonyl)piperidine, and then the resultant was used in the method of Example 1-1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Product: O=C(c1ccc(S(=O)(=O)N2CCOCC2)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 35.8 %

Procedure:
The title compound is prepared from 4-(morpholine-4-sulfonyl)-benzoic acid (407 mg, 1.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (CAS 51207-66-0)(193 mg, 1.2 mmol) in a manner substantially similar to Procedure G to provide 175 mg (34%) of the title compound. MS (ES+) 408.3 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:9]>>[CH:7]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2]=2[CH:1]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1
Reactant: C#CCCCC#C
Reactant: CCOC(=O)C#N
Product: CCOC(=O)c1cc2c(cn1)CCC2
Yield: 20.6 %

Procedure:
A solution of 1,6-heptadiyne (1.242 ml, 10.85 mmol) and ethyl cyanoformate (1.063 ml, 10.85 mmol) in dry degassed 1,4-dioxane (100 ml) under argon at rt was treated with cyclopentadienyl-Cobalt(I)-dicarbonyl (0.293 g, 1.628 mmol) and then heated at reflux for 18 h. Reaction was then evaporated, treated with toluene (100 ml), re-evaporated, dissolved in DCM (100 ml), filtered through a short pad of Kieselguhr, eluting with DCM, organic extracts evaporated, chromatographed (0-100% DCM:40-60 Petroleum ether then 0-10% methanol/DCM) to give product as an impure brown oil (427 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18].C1(O)C=CC=CC=1>CC(C)=O>[ClH:1].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: CN(C)CCN
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: Cc1cc(NCCN(C)C)c2cccc(O)c2n1
Product: Cl
Temperature: 125 °C
Yield: 57 %

Procedure:
A mixture of 4-chloro-8-hydroxy-2-methylquinoline (500 mg), N,N-dimethylethylenediamine (341 mg) and phenol (486 mg) was heated at 125° C. for 18 hours. After cooling the reaction mixture, acetone (5 ml) was added thereto. The precipitates were collected by filtration and recrystallized from acetonitrile to give 4-(2-dimethylaminoethylamino)-8-hydroxy-2-methylquinoline hydrochloride (415 mg)) as brown crystals.