Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18])[CH3:12]>N1CCCCC1.C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:21][C:20]=1[CH3:27])=[O:18])[CH3:29]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Yield: 55.5 %

Procedure:
A mixture of 1,3-dihydro-indol-2-one (266 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90° C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 422 mg (55%) of the title compound as a light yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:47]=[CH:46][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl.O1CCOCC1>ClCCl>[NH2:8][CH2:9][C:10]1[CH:47]=[CH:46][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:43])([CH3:44])[CH3:42])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:31])[F:32])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCOC(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCCCn1c(Cn2c(=O)n(CC(F)(F)F)c(=O)c3ccccc32)nc2cc(CN)ccc21
Yield: 92.4 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 4-{5-(tert-butoxycarbonylamino-methyl)-2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-benzoimidazol-1-yl}-butyl ester (59 mg, 0.089 mmol) and TFA (138 μL, 1.79 mmol) in dichloromethane (2 mL) was stirred for 4 hrs at room temperature. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. A solution of 4N HCl in dioxane (233 μL, 10 equiv.) was added, followed by concentration. The residue was triturated from diethyl ether and filtered to give the title compound (46 mg, 87%) as a tan solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].I[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1N(c2ccc(C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Temperature: 120 °C
Yield: 23.7 %

Procedure:
As an alternative, this material was prepared through a palladium-catalyzed coupling in analogy to a procedure described in literature: W. E Shakespeare, Tetrahedron Lett. 1999, 40 p 2035): A mixture of 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.085 g), palladium(II) acetate (0.012 g), 1,1′-bis(diphenylphosphino)-ferrocene (0.021 g) was treated under an argon atmosphere at RT with 4-iodobenzotrifluoride (0.211 g in toluene, 5 ml) and sodium tert-butoxide (0.142 g). More toluene (5 ml) was added and the mixture was then heated at 120° C. for 23 h. It was then cooled to RT, diluted with AcOEt and filtered through Celite. The filtrate was washed with aqueous NH4Cl, brine, dried over Na2SO4 and concentrated onto silica gel. Flash chromatography (eluent; MeOH/CH2Cl2 0 to 5%) gave the desired compound as a light brown solid (0.029 g). 473.1 (MH+)
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]3[N:29]=[C:28]4[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]4)=[CH:22][CH:21]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:29]=[C:28]4[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]4)=[CH:22][CH:21]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc(N2CCN(CCCC=Cc3ccc4c(n3)NC(=O)CC4)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: CCc1cccc(N2CCN(CCCCCc3ccc4c(n3)NC(=O)CC4)CC2)n1
Yield: 0.9 %

Procedure:
7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.515 g, 1.27 mmol) was hydrogenated using 20% Pd/C in EtOH for 103 h. The reaction was filtered and concentrated. Purification by liquid chromatography (Biotage 12 SiO2 column, CH2Cl2 to 1% MeOH/CH2Cl2) followed by recrystallization from Et2O gave the title compound as a solid (50 mg, 0.012 mmol, 10%). MS: APCI: M+1: 408.2 (Exact Mass: 407.27).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (372 mg, 75%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: Oc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1ccccc1

Procedure:
Phenol (0.5 mole) was added to a solution of sodium ethoxide in ethanol (2 N; 250 ml) and 1-bromobutane (0.5 mole) was added dropwise while stirring. The mixture was heated under reflux for three hours and most of the solvent was then distilled off. Water was added to the residue and the organic layer was separated, washed twice with 10% aqueous NaOH, water, dilute H2SO4 and water, and was then dried over MgSO4. It was distilled in vacuo to give the title compound, b.p. 88°-91° C. at 14 mm Hg pressure. The identity and purity was confirmed by thin layer chromatography (TLC) and NMR and IR spectroscopy.
Reaction SMILES: FC1C(O[C:9]([C:11]2([F:30])[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[CH3:29])=[CH:19][C:14]3=[N:15][CH2:16][N:17]([CH3:18])[C:13]3=[CH:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.Cl.[NH2:36][NH2:37].C(N(CC)CC)C.O>ClCCl>[F:30][C:11]1([C:9]([NH:36][NH2:37])=[O:10])[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[CH3:29])=[CH:19][C:14]2=[N:15][CH2:16][N:17]([CH3:18])[C:13]2=[CH:12]1
Reactant: Cc1cc(I)ccc1NC1=CC2=NCN(C)C2=CC1(F)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(I)ccc1NC1=CC2=NCN(C)C2=CC1(F)C(=O)NN
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a stirring suspension of 5-fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid pentafluorophenyl ester (0.223 g, 0.355 mmol) and hydrazine hydrochloride (0.026 g, 0.355 mmol) in dichloromethane (10 mL) was added triethylamine (0.11 mL, 0.554 mmol). After stirring for 16 hours at ambient temperature, water was added to the reaction mixture. The afforded solids were filtered off and washed several times with water. The solids were dried under house vacuum at 60° C., which afforded 5-fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrazide as a white solid (0.050 g, 42.4%). mp=232–234° C.; APCI+440.1; 1H NMR (400 MHz, DMSO-D6) δppm 2.3 (s, 3 H) 3.9 (s, 3 H) 6.2 (m, 1 H) 5.3 (m, 1 H) 5.3 (s, 2 H) 5.4 (s, 1 H) 5.5 (s, 1 H) 5.9 (s, 1 H) 8.3 (s,1 H). Step B: To a stirring solution of 5-fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrazide (0.055 g, 0.125 mmol) in dioxane (5 mL) was added cyanogen bromide (0.015 g, 0.138 mmol) and NaHCO3 (0.12 g, 0.138 mmol) in water (1 mL) and the mixture was allowed to stir overnight at ambient temperature. To the reaction mixture was added saturated NaHCO3 and the afforded solids were filtered and washed with water. The solids were collected and dried in vacuo at 50° C. to afford [6-(5-amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1-methyl-1H-benzoimidazol-5-yl]-(4-iodo-2-methyl-phenyl)-amine (0.051 g, 88%). mp=258–260° C.; APCI+=465.0; 1H NMR (400 MHz, DMSO-D6) δ ppm 2.2 (s, 3 H) 3.8(s,3 H) 4.5 (s,2 H) 6.1 (m,1 H) 5.2 (d, J=9.0 Hz, 1 H) 5.4 (d, J=1.5 Hz, 1 H) 5.5(s, 1 H) 8.1 (s, 1 H) 8.3 (s, 1 H) 9.8 (s,1 H).
Reaction SMILES: C(CN)O.C(CCCCC[C:13]1[N:18]2[CH:19]=[N:20][CH:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)(O)=O>>[CH:21]1[N:20]=[CH:19][N:18]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=12
Reactant: O=C(O)CCCCCc1cccc2cncn12
Solvent: NCCO
Product: c1ccn2cncc2c1

Procedure:
Ethanolamine (6.1 g) and 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine (2.32 g) are heated at 170° for 3 hours. Excess ethanolamine is removed by distillation under reduced pressure to yield 5-[5-(4,5-dihydrooxazol-2-yl)pentyl)]imidazo[1,5-a]pyridine.
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[C:12]([CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH2:29][C:30]4[C:31]([O:37][CH3:38])=[N:32][CH:33]=[C:34]([F:36])[CH:35]=4)=[N:26][CH:27]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:36][C:34]1[CH:35]=[C:30]([CH2:29][NH:28][C:25]2[N:26]=[CH:27][C:22]([CH2:21][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=4)[NH:10][CH:11]=3)=[CH:23][N:24]=2)[C:31]([O:37][CH3:38])=[N:32][CH:33]=1
Reactant: COc1cnc2c(c1)c(Cc1cnc(NCc3cc(F)cnc3OC)nc1)cn2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc2[nH]cc(Cc3cnc(NCc4cc(F)cnc4OC)nc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [5-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine (125, 1 equivalent) in 15.0 mL of tetrahydrofuran, tetrabutylammonium fluoride trihydrate (2 equivalent) is added. The reaction is stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH2:9][C:8]2=[O:16])=[O:4].C([O:22][N:23]=O)CCC.Cl>CO.O1CCOCC1>[CH3:17][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][C:9](=[N:23][OH:22])[C:8]2=[O:16])=[O:4]
Reactant: COc1cc2c(cc1C(=O)N(C)C)C(=O)CC2
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1C(=O)N(C)C)C(=O)C(=NO)C2
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 6-Methoxy-3-oxo-indan-5-carboxylic acid dimethylamide (2.56 g, 10.97 mmol) in the methanol (40 ml) and dioxane (40 ml) was added n-butylnitrite (1.48 ml, 12.067 mmol) followed by concentrated HCl (1 ml). The solution was stirred at r.t overnight during which time a precipitate was formed. The precipitate was collected and dried to yield a yellow solid (2.8 g, 97%). LC-MS: m/e 263 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:41])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([OH:40])=O)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[CH:59]1([NH:62][C:63]([C@@H:65]2[CH2:69][CH2:68][CH2:67][NH:66]2)=[O:64])[CH2:61][CH2:60]1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:41])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:66]3[CH2:67][CH2:68][CH2:69][C@H:65]3[C:63](=[O:64])[NH:62][CH:59]3[CH2:60][CH2:61]3)=[O:40])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccccc3n2)CC1
Reactant: O=C(NC1CC1)[C@@H]1CCCN1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CC3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.2 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of DMF, 883 mg of EDC, 848 mg of pentafluorophenol and 885 mg of NEM was added and the reaction mixture was stirred for 2 h at RT. Then, 732 mg of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 442 mg of NEM in 5 ml of DMF was added. After 2 h the reaction mixture was diluted with water and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 2.9 g.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][C:22]([CH2:27][S:28][CH3:29])([CH2:25][OH:26])[CH2:23][OH:24])=[CH:11]1)C1C=CC=CC=1.Cl.[NH2:31]N.ClCCl>N.[Pd]>[NH2:31][C:17]1[C:18]2[NH:10][CH:11]=[C:12]([CH2:20][NH:21][C:22]([CH2:27][S:28][CH3:29])([CH2:25][OH:26])[CH2:23][OH:24])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: NN
Reactant: CSCC(CO)(CO)NCc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Agent: [Pd]
Agent: Cl
Agent: N
Solvent: ClCCl
Product: CSCC(CO)(CO)NCc1c[nH]c2c(N)ncnc12
Yield: 36.4 %

Procedure:
To a suspension of 2-((5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (9.0 mg, 0.037 mmol) and palladium-black (10 mg) in 7 M methanolic ammonia (2 mL) was added hydrazine hydrochloride (0.250 mL, 6.87 mmol) dropwise. After 1 h at ambient temperature the reaction was virtually complete by TLC (dichloromethane:7 M methanolic ammonia, 3:1, visualised with UV and Erlichs). The supernatant solution was filtered through a small pad of celite and the palladium was washed twice with methanol and also filtered through celite. The combined filtrates were concentrated under reduced pressure and the resulting residue triturated with chloroform and dichloromethane. Lyophilization of the residue gave 2-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (4 mg, 63%) as a white solid. 1H NMR (D2O) δ 8.16 (s, 1H), 7.58 (s, 1H), 4.12 (s, 2H), 3.79-3.70 (m, 4H), 2.85 (s, 2H), 2.15 (s, 3H). +ESMS Found 298.1346 (M+H+) C12H20N5O2S requires 298.1338.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[NH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([N:78]4[CH2:83][CH2:82][O:81][CH2:80][CH2:79]4)=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:12]=1)[CH3:25]
Reactant: C1COCCN1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3cc(N4CCOCC4)ccc3c2n1CCCOC(C)C
Temperature: 80 °C

Procedure:
7-Bromo-2-ethoxymethyl-1-(isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (1.0 g), (+)-2,2′-bis(diphenylphosphino)-1,1′binaphthyl (BINAP, 0.089 g), tris(dibenzylideneacetone)dipalladium(0) (0.074 g), sodium tert-butoxide (0.320 g,), morpholine (0.230 mL,) and toluene (4.8 mL) were added to a scintillation vial. The vial was sequentially flushed with nitrogen, sealed with a Teflon-lined cap, placed in an oil bath, and heated at 80° C. for 16 hours. The reaction mixture was cooled to ambient temperature and then transferred to a round bottom flask. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on a Biotage Horizon™ High Performance Flash Chromatography instrument using a silica gel cartridge. The purification was carried out eluting with chloroform:CMA in a gradient from 98:2 to 75:25. 2-Ethoxymethyl-1-(3-isopropoxypropyl)-7-(morpholin-4-yl)-1H-imidazo[4,5-c]quinoline was isolated as a red-orange oil (1.32 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[I-].[K+].Br[CH2:17][CH2:18][O:19][CH3:20]>CN(C=O)C>[CH3:20][O:19][CH2:18][CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: COCCBr
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Indole-3-carbaldehyde (1 eq.) was dissolved in DMF (0.46 M). Sodium hydride was added (1.3 eq.) and the resulting solution was stirred at RT for 20 min. Potassium iodide (1 eq.) and 1-bromo-2-methoxyethane (2 eq.) were then added and the reaction solution was allowed to stir at RT for 48 h. The reaction mixture was subsequently quenched with brine and extracted with EtOAc. The combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as an orange oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@H:11]([CH2:14][CH3:15])[CH2:12][OH:13])=[N:6][C:7]=1[CH2:8][CH3:9].[C:18](OCC)(=O)C>CCCCCCC>[Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@@H:11]([CH2:12][O:13][CH3:18])[CH2:14][CH3:15])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@H](CC)CO)c(CC)nc1Br
Reactant: CCOC(C)=O
Solvent: CCCCCCC
Product: CCc1nc(N[C@H](CC)COC)c(CC)nc1Br
Yield: 42 %

Procedure:
Following the general procedure of Example 13 Step 3 and making non-critical variations but substituting (2S)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol with (2R)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol (Example 12 Step 2) (353 mg, 1.17 mmol) gave 154 mg (42%) of 5-bromo-3,6-diethyl-N-[(1R)-1-(methoxymethyl)propyl]pyrazin-2-amine as a yellow oil after Biotage MPLC (40 g column, 20% ethyl acetate in heptane).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=O)=[O:9].[NH2:16][C:17]1[C:26]([CH3:27])=[C:25]([Cl:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:31][CH3:32])[C:21]([O:29][CH3:30])=[N:22]2.O>O1CCCC1.C(OCC)(=O)C>[Cl:28][C:25]1[CH:24]=[C:23]2[C:18]([N:19]=[C:20]([O:31][CH3:32])[C:21]([O:29][CH3:30])=[N:22]2)=[C:17]([NH:16][S:8]([CH3:7])(=[O:11])=[O:9])[C:26]=1[CH3:27]
Reactant: COc1nc2cc(Cl)c(C)c(N)c2nc1OC
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc2cc(Cl)c(C)c(NS(C)(=O)=O)c2nc1OC
Reaction time: 1 h
Yield: 101 %

Procedure:
Pyridine (80 μl, 78 mg, 0.985 mmol) and methanesulphonic anhydride (172 mg, 0.985 mmol) were added to a solution of 5-amino-7-chloro-2,3-dimethoxy-6-methylquinoxaline (50 mg, 0.197 mmol) in dry tetrahydrofuran (1.6 ml) at room temperature under nitrogen. After stirring for 17 hours water (0.3 ml) was added and stirring continued for 1 hour. The mixture was diluted with ethyl acetate (15 ml) and washed with 2M hydrochloric acid (5 ml), water(5 ml), saturated sodium bicarbonate solution (5 ml) and brine (5 ml) and then dried (MgSO4), filtered and concentrated under reduced pressure to afford N-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)methanesulphonamide (66 mg, 100%) as a white solid mp 228°-229° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:39](O)=[O:40])=[CH:24][C:25]=3[N:26]3[CH2:32][C@H:31]([OH:33])[C@H:30]([OH:34])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:42][N:43]([CH3:48])[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:39]([NH:47][S:44]([N:43]([CH3:48])[CH3:42])(=[O:46])=[O:45])=[O:40])=[CH:24][C:25]=3[N:26]3[CH2:32][C@H:31]([OH:33])[C@H:30]([OH:34])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (12.6 mg, 0.066 mmol) was added to a solution of 13-cyclohexyl-6,7-dihydro-(5R,6S)-rel-5,6-dihydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (8.7 mg, 0.022 mmol) and DMAP (8.1 mg, 0.066 mmol) in DMF (0.3 mL) and CH2Cl2 (0.3 mL) at 22° C. The vial was shaken for a minute at 22° C. then N,N-dimethylsulfamide (5.5 mg, 0.044 mmol) was added. Stirring was continued for 18 hr. The solution was then filtered and purified by Prep. reverse phase chromatography. The product containing fraction was concentrated on a Speed Vac® to leave the title compound as a white film (1.2 mg, 11%). ESI-MS m/z 498 (MH+) 1H NMR (500 MHz, MeOD) δ 1.23-1.33 (m, 1 H) 1.39-1.54 (m, 2 H) 1.62 (m, 1 H) 1.77-1.87 (m, 2 H) 1.93-2.18 (m, 4 H) 2.99 (d, J=11.29 Hz, 1 H) 3.04 (s, 6 H) 3.35 (m, 1 H) 4.42 (d, J=4.58 Hz, 1 H) 4.56 (m, 1 H) 4.75 (dd, J=14.50, 7.17 Hz, 1 H) 7.47 (m, 2 H) 7.54 (m, 1 H) 7.61 (dd, J=8.55, 1.53 Hz, 1 H) 7.80 (d, J=7.63 Hz, 1 H) 7.94 (d, J=8.85 Hz, 1 H) 8.13 (s, 1 H).