Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(O)(=O)C>[Zn].O>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
385.0 mg (1.05 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzothio-phene-2-carboxamide hydrochloride are suspended in 10 ml of a 1:1 mixture of acetic acid and water. 300.0 mg (4.59 mmol) of zinc are added, and the mixture is then stirred at RT for 1 h. The reaction mixture is filtered through kieselguhr, and the filter cake is washed with methanol. The filtrate is concentrated under reduced pressure and the residue is purified by preparative HPLC. The product fraction is dissolved in 4M HCl in dioxane, concentrated under reduced pressure and recrystallized from acetonitrile. 233 mg (59.5% of theory) of the title compound are obtained.
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[N:21][OH:22])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[O:6]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=2)[O:22][N:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3cccc(Oc4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 28.7 %

Procedure:
To a tetrahydrofuran (10.0 mL) solution of (3-phenoxy-phenyl)-acetohydroximoyl chloride (133 mg, 0.508 mmol) described in Manufacturing Example 64-1-3 and 3-ethynyl-pyridine-2,6-diamine (30.0 mg, 0.254 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 14 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:1) to obtain the title compound (26.1 mg, 80.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][C:3]=1[F:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2([C:38](O)=[O:39])[CH2:37][CH2:36]2)=[O:34])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:35]5([C:33]([NH:32][C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=6)=[O:34])[CH2:37][CH2:36]5)=[O:39])=[C:3]([F:24])[CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1F
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
To a solution of N-[6-(4-amino-3-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) in N,N-dimethylacetamide (3.0 mL) were added 1-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (170 mg, 0.689 mmol), HATU (262 mg, 0.689 mmol) and N,N-diisopropylethylamine (120 μL, 0.689 mmol), and the mixture was stirred at room temperature for 20 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate alone). The obtained powder was washed with hexane/ethyl acetate and collected by filtration to give the title compound (115 mg, 47%) as a white solid.
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=1>O1CCCC1>[C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([S:4][CH:1]([CH3:3])[CH3:2])[N:9]=1)#[N:15]
Reactant: CC(C)S
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Sc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
Isopropyl mercaptan (0.60 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.40 g, ca. 100%) as an oil.
Reaction SMILES: [C:1]1(=[O:10])[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH:2]12.Br[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[N:16][CH:17]=1>>[N+:18]([C:15]1[N:16]=[CH:17][C:12]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][CH2:8][CH2:9][CH:2]3[C:1]2=[O:10])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=C1NCCN2CCCC12
Product: O=C1C2CCCN2CCN1c1ccc([N+](=O)[O-])nc1
Yield: 42.8 %

Procedure:
Following general N—C coupling procedure 1, hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.202 g, 1.44 mmol), was combined with 5-bromo-2-nitropyridine (0.293 g, 1.44 mmol, 1.0 eq) which gave 2-(6-Nitro-pyridin-3-yl)hexahydro-pyrrolo[1,2-a]pyrazin-1-one as a tan solid (0.170 g, 0.616 mmol) in 43% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.79-2.19 (m, 1H) 2.31 (br. s., 1H) 2.77 (br. s., 1H) 2.98-3.16 (m, 1H) 3.26 (dt, J=12.05, 4.52 Hz, 1H) 3.47 (br. s., 1H) 3.80 (br. s., 1H) 3.95-4.23 (m, 1H) 8.15 (dd, J=8.53, 2.51 Hz, 1H) 8.32 (d, J=8.53 Hz, 1H) 8.70 (d, J=2.51 Hz, 1H). MS m/z 263.1 (M+H)+.
Reaction SMILES: C[OH:2].[C:3]([O:6][CH3:7])(=[O:5])[CH3:4].O.[C:9](O)(=O)[CH3:10]>>[CH:4](=[O:2])[C:3]1[O:6][CH:7]=[CH:10][CH:9]=1.[C:3]([O:6][CH3:7])(=[O:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CO
Solvent: O
Solvent: COC(C)=O
Product: O=Cc1ccco1

Procedure:
At this point vaporized methanol is started down the top of column 14d via lines 28d, 48d. By virtue of the fact that there is little acetic acid present in column 14d, there is little heat of reaction from the formation of methyl acetate. Therefore, downward travel of methanol is continued until the vapor breaks through adjacent bottom of column 14d, (as indicated by the temperature reading of probe 15d), whereupon upward travel thereof is commenced by delivery of addition quantities of methanol through line 28d. During downflow of methanol within column 14d, furfural, water, a minor amount of acetic acid and any polymerized materials present pass through line 30d to tank 32d, and any methyl acetate formed will condense as the column heats up and similarly be forced out of column 14d. The secondary upward travel of methanol vapor and downward travel of methanol liquid within column 14d completes the removal of furfural such that the column is essentially loaded with methanol. The originally adsorbed furfural is at this point collected in tank 32 d.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[CH:22]=[C:21]([CH2:28][CH2:29][CH3:30])[CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>O=[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[C:21]([CH2:28][CH2:29][CH3:30])[CH:22]=[C:23]([CH2:25][CH2:26][CH3:27])[CH:24]=3)[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: O=[Pt]=O
Product: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c1

Procedure:
In the manner given in Example 1B, 1-[(p-nitrophenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine is reduced with hydrogen over PtO2 to give 1-[(p-amino-phenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].N1C=CC=CC=1.O>ClCCl>[Br:19][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(Br)ccc1NC(=O)OC(C)C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
Add isopropyl chloroformate (36.9 mL, 36.9 mmol, 1.0 M in toluene) dropwise to a solution of methyl 2-amino-5-bromobenzoate (5.0 g, 24.6 mmol) and pyridine (80.0 mL, 36.9 mmol) in dichloromethane (80 mL) at room temperature under an atmosphere of nitrogen and stir for 1.5 h. Pour the reaction into water (100 mL) and separate the layers. Extract the aqueous layer with dichloromethane (2×40 mL) and combine the organic extracts and wash with 2 N hydrochloric acid, saturated sodium hydrogen carbonate, and brine (80 mL each). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to afford the title compound as a pale yellow solid (6.68 g, 86%). 1H NMR (CDCl3) δ 1.31 (d, J=6.3 Hz, 6H), 3.92 (s, 3H), 5.03 (septet, J=6.3 Hz, 1H), 7.61 (dd, J=1.9, 8.5 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 10.31 (br s, 1H). ESI MS m/z 316 [C12H14BrNO4+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]=[O:18])=[CH:13][CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: O=CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of the compound obtained from step d above (0.7 g) in dichloromethane (10 mL), 2,2,6,6-tetramethylpiperidine N-oxyl (4.36 mg) and potassium bromide (33.32 mg) were added at 0° C. under nitrogen atmosphere. Sodium hypochlorite (6.5 mL, 4% solution) was added at pH 8-9 (maintained by adding aqueous sodium bicarbonate solution). The reaction was stirred for 20 minutes at 0° C. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (0.57 g).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([C:46](=[O:48])[CH3:47])[CH:43]=[CH:44][CH:45]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](=[O:48])[CH3:47])[CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 22.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (6.22 g), 3′-bromoacetophenone (2.30 g) and tetrakis(triphenylphosphine)palladium(0) (0.210 g), the title compound (1.50 g) was obtained as colorless powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: Clc1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccn2c(Br)cnc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Chloro-imidazo-[1,2-a]-pyridine (1 eq, 38.9 mmol, 5.93 g) is dissolved in DMF (20 ml) at 0° C. and NBS (1.1 eq, 42.8 mmol, 7.61 g) is added. The reaction mixture is stirred for 1 h at 0° C. and is diluted with EtOAc. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 3-bromo-7-chloro-imidazo-[1,2-a]-pyridine as a brown solid; [M+H]+=232
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)([CH3:38])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH:32]1[S:37][CH2:36][CH2:35][CH2:34][S:33]1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1)([CH3:21])[C:16](OCC)=[O:17])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([C:5]([CH3:38])([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH:32]2[S:33][CH2:34][CH2:35][CH2:36][S:37]2)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)([CH3:21])[CH2:16][OH:17])[CH2:4][OH:3])=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CCOC(=O)C(C)(CCCCC(CCCCC(C)(C(=O)OCC)c1ccc(CC(C)C)cc1)C1SCCCS1)c1ccc(CC(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)(CO)CCCCC(CCCCC(C)(CO)c2ccc(CC(C)C)cc2)C2SCCCS2)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A solution of 212f (5.81 g, 8.33 mmol) in freshly distilled THF (50 mL) was added dropwise to a suspension of LiAlH4 (1.0 g, 26.4 mmol) in THF (50 mL) at −78° C. under a nitrogen atmosphere. The solution was warmed to room temperature over 4 h, then cooled back to −78° C., and quenched with ethyl acetate (5.0 mL). After warming to room temperature, water (100 mL) was added and the product was extracted with Et2O (2×100 mL). The ether extracts were combined, dried with sodium sulfate, filtered, and concentrated. After drying under high vacuum for 4 h, 213f (4.80 g, 94%) was obtained as a colorless oil. 1H NMR (CDCl3): δ 7.20 (d, 4H, J=8.0), 7.09 (d, 4H, J=8.0), 3.64 (d, 2H, J=10.7), 3.48 (d, 2H, J=10.7), 2.71 (t, 4H, J=5.1), 2.50-2.35 (m br., 2H), 2.43 (d, 4H, J=7.0), 1.90-1.80 (m, 4H), 1.80-1.68 (m, 6H), 1.58-1.42 (m, 2H), 1.38-1.25 (m, 4H), 1.30 (s, 6H), 1.26-1.10 (m, 2H), 1.10-0.95 (m, 2H), 0.89 (d, 12H, J=6.6). 13C NMR (CDCl3): δ 141.94, 139.39, 129.20, 126.44, 72.48, 53.30, 44.97, 43.09, 38.45, 38.18, 30.21, 26.01, 25.64, 24.84, 24.09, 22.55, 21.64. HRMS (LSIMS, nba): Calcd for C38H61O2S2 (MH+): 613.4113, found: 613.4075. HPLC: 97.6% pure.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24][CH3:25])[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].I[CH2:28][CH3:29].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[C:12]([O:24][CH3:25])=[N:11][C:10]3[C:14]2=[N:15][C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[N:8][C:9]=3[NH2:26])[CH2:19]1)[CH3:29]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: CCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1

Procedure:
A solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (45 mg, 0.124 mmol), iodoethane (0.012 ml, 0.149 mmol) and triethylamine (0.035 mL, 0.248 mmol) in DMF (3 ml) was heated at 50° C. for 18 hours.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[IH:33]>C(OCC)C>[IH:33].[F:26][C:23]([F:24])([F:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Agent: I
Solvent: CCOCC
Solvent: CO
Product: FC(F)(F)CCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.80 g, 4.22 mmol) and methanol (15 mL). Cool in an ice bath. Add aqueous hydriodic acid (3.8 g, 2.23 mL, 57%, 16.9 mmol) and warm to ambient temperature. After 30 minutes, add aqueous hydriodic acid (1.12 mL) and heat to 50° C. After 2 hours, cool to ambient temperature and evaporate to remove most of the methanol to give a residue. Combine the residue and methanol (10 mL). Add diethyl ether (200 mL) and stir to give a solid. Decant the solvent, add diethyl ether (200 mL) and stir, collect the solid by filtration to give, after drying, the title compound: mp; 206-208° C.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][C:61]=1[C:69]([F:72])([F:71])[F:70]>>[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][C:61]=1[C:69]([F:70])([F:71])[F:72]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 74 %

Procedure:
The compound of example 205 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-fluoro-3-trifluoromethyl benzoyl chloride.
Reaction SMILES: [C:1]([NH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([OH:18])=[O:17])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CC(C)([O-])C.[K+]>>[CH2:2]([C:1]1[NH:12][C:13]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Yield: 72.6 %

Procedure:
A mixture of 3-(n-decanamido)-4-methylbenzoic acid (6.0 g) and potassium tert-butoxide (23.5 g) was treated in a similar manner to that described hereinbefore in Example 1 to give a solid which was recrystallised from ethanol to give 2-(n-nonyl)indole-6-carboxylic acid (4.1 g), in the form of colourless crystals, m.p. 166°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]1([OH:30])[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]2([OH:30])[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCC(O)(CN)CC1
Product: CN1CCC(O)(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-(aminomethyl)-1-methylpiperidin-4-ol (14.4 mg, 0.1 mmol). The title compound was obtained as a solid (15.2 mg, 32% yield). MS m/z: 476.87, 478.86 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].I[CH3:30].[Cl-].[NH4+]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[N:17]([CH3:30])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (80% disp. in oil, 130 mg, 4.2 mmol) in dry N,N-dimethylformamide (6 ml) under nitrogen was added dropwise a solution of (±) cis-1-(3,4-dichlorobenzyl)-2-tert-butoxycarbonylaminoindane (1.65 g, 4.2 mmol) in N, N-dimethylformamide (10 ml). After stirring the mixture for 30 minutes at room temperature, iodomethane (0.28 ml, 4.5 mmol) was added dropwise and stirring continued for a further 1 h. The reaction mixture was then poured into a large excess of sat. ammonium chloride and extracted with diethyl ether (3×40 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford the title compound as a colourless oil (1.02 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[N:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 60.7 %

Procedure:
A solution ethyl 3-aminoindole-2-carboxylate (4.94 g, 24.2 mmole) and 4-chloropyridine hydrochloride (3.63 g, 24.2 mmole) in 70 mL of 1-methyl-2-pyrrolidinone was heated at 165° C. for 6 hours. The reaction mixture was then quenched into water and the aqueous phase was washed with ethyl acetate. After basification with a potassium carbonate solution, a solid was filtered, rinsed with water and ether and dried to give 4.13 g of a brown solid. A 2.2 g portion was recrystallized from methanol (charcoal treatment) to give 1.40 g of an off-white solid, mp: 248-250° C. (dec.)