Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH:4]([CH3:9])[C:5](=[O:8])[CH2:6][CH3:7].Br[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.[Mg]>>[ClH:18].[Cl:19][C:14]1[CH:13]=[C:12]([C:5]([OH:8])([CH2:6][CH3:7])[CH:4]([CH3:9])[CH2:3][N:2]([CH3:10])[CH3:1])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCC(=O)C(C)CN(C)C
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Mg]
Product: CCC(O)(c1ccc(Cl)c(Cl)c1)C(C)CN(C)C
Product: Cl
Yield: 43.7 %

Procedure:
39 g of crude mixture were prepared analogously to Example 1 from 15 g (105 mmol) 1-dimethylamino-2-methylpentan-3-one, 35.5 g (157 mmole) 4-bromo-1,2-dichlorobenzene and 3.8 g (157 mmole) magnesium turnings. This mixture was introduced on to a 7×40 cm column packed with silica gel and eluted with 4:1 ethyl acetate/methanol. 14.9 g of base were obtained, from which 11.2 g of hydrochloride (2) (31% theoretical) with a melting point of 183-184° C. were obtained with trimethylchlorosilane/water in 2-butanone/diisopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>CO.C(OCC)C.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:26])=[O:12])=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(Br)cc1

Procedure:
To a solution of (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid from step 2 example 1, (2.5 g, 6.6 mmol) in methanol (25 mL) at 0° C. was added portionwise diazomethane in diethyl ether until the yellow color persisted. A few drops of acetic acid were then added to quench the excess diazomethane. The colorless solution was concentrated and then the volatiles were coevaporated twice with n-heptane. The oil was pumped on to remove the last traces of solvent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][C:9]([C:11]1[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:12]=1[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]1)=[O:20])=[O:10])([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][C:9]([C:11]1[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:12]=1[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]1)=[O:20])=[O:10]
Reactant: CCc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(NC(=O)C2CCC(C(=O)O)CC2)s1
Agent: [Ni]
Solvent: CO
Product: CCc1cc(C(=O)NCc2cccc(N)c2)c(NC(=O)C2CCC(C(=O)O)CC2)s1

Procedure:
A solution of 4-{3-[(3-nitrobenzyl)carbamoyl]-5-ethylthiophen-2-ylcarbamoyl}cyclohexanecarboxylic acid in methanol is hydrogenated in the presence of Raney nickel. The catalyst is filtered off and the solution is concentrated. After recrystallization, 4-{3-[(3-aminobenzyl)carbamoyl]-5-ethylthiophen-2-ylcarbamoyl}cyclohexanecarboxylic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
3,4-Dichloroaniline, 13.7 g (0.084 mole), is dissolved in 200 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoyl chloride, 14.6 g (0.086 mole), is added slowly. The solution is stirred two hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. A crude product is crystallized from 95% ethanol. There is obtained N-(3,4-dichlorophenyl) nonanamide, a white crystalline solid, (M.P. 68.5-69.0%). Analysis shows 4.52% nitrogen and 23.26% chlorine as against calculated values of 4.63% and 23.48% respectively for C15H21Cl2NO.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](O)=[O:37].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:33]([O:32][CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH:34]=2)[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1OC

Procedure:
A mixture of ((3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.9 g, 23.02 mmol), 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid (6.08 g, 25.32 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (6.45 g, 25.32 mmol) and triethylamine (7.62 mL, 92.07 mmol) in CH2Cl2 (230 mL) is refluxed for 3 h. The reaction is quenched by the addition of an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/acetone 95:5 to CH2Cl2/MeOH 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.47. MS (LC-MS): 609.4 [M+H]+; tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 7.05 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:19]([F:24])[CH:18]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2c1

Procedure:
The method of Example 281 was used with 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile, 174.7 mg (1.2 mmol) of 4-chloro-2-fluoro-aniline and 115.6 mg (1 mmol ) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol. This afforded 319.8 mg of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 325.9, 327.9
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:17]([CH3:28])([CH3:27])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>C1(C)C(C)=CC=CC=1.O>[CH2:10]([N:14]([CH:15]1[CH2:16][C:17]([CH3:28])([CH3:27])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:19]([CH3:21])([CH3:22])[CH2:20]1)[C:8]1[N:1]=[C:2]([N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]2[CH2:16][C:17]([CH3:27])([CH3:28])[N:18]([O:23][CH2:24][CH2:25][CH3:26])[C:19]([CH3:22])([CH3:21])[CH2:20]2)[N:4]=[C:5]([Cl:6])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCNC1CC(C)(C)N(OCCC)C(C)(C)C1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(OCCC)C(C)(C)C2)n1)C1CC(C)(C)N(OCCC)C(C)(C)C1
Reaction time: 1.5 h

Procedure:
A four-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, dropping funnel and condenser is charged with 27.3 g (0.148 mol) of cyanuric chloride and 200 mL of xylene at 0-5° C. 40 g (0.148 mol) of compound I-102 in 25 mL of xylene are slowly added over 20 minutes to this solution. After 90 minutes, further 40 g (0.148 mol) of compound I-102 in 25 mL of xylene and 25 mL of water are slowly added over 20 minutes to the system allowing the temperature to reach 45° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][C:22]([C:28]#[N:29])=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6].C(C1C=C(C(C)C)C2OC(C3C=CC(C(O)=O)=CC=3)=NC=2C=1)#N>>[C:28]([C:22]1[CH:23]=[C:24]([CH:25]([CH3:27])[CH3:26])[C:18]2[O:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:31])=[O:2])=[O:30])=[CH:11][CH:12]=3)=[N:20][C:19]=2[CH:21]=1)#[N:29]
Reactant: COC(=O)C(NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1)C(C)C
Agent: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC(C(=O)O)C(C)C)cc3)oc12

Procedure:
The title compound was prepared from methyl-2-{[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}-3-methylbutanoate (EXAMPLE 29) using procedure analogous to that described in INTERMEDIATE 2, Step C. Mass spectrum (ESI) 406.20 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.19 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.79 (d, J=1.4 Hz, 1H), 7.38 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 4.59 (m, 1H), 3.45 (m, 1H), 2.2 m, 1H), 1.32 (d, J=7.10 Hz, 6H), 0.91 (t, J=6.3 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:51])[C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.N1(C2C=C(NC(N3C4N=C(N5CCOCC5)N=C(C5C=NC(N(CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=NC=5)C=4CC3)=O)C=CC=2)CCOCC1>>[CH3:51][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH:3]=1)[C:9]([N:11]1[C:15]2[N:16]=[C:17]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[N:18]=[C:19]([C:20]3[CH:21]=[N:22][C:23]([NH2:26])=[N:24][CH:25]=3)[C:14]=2[CH2:13][CH2:12]1)=[O:10]
Reactant: C1COCCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3cccc(Br)c3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(N4CCOCC4)c3)cn2)cc1
Product: CN(C(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21)c1cccc(N2CCOCC2)c1
Yield: 61.3 %

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide (112 mg) and morpholine (15.5 mg) instead of 2-piperazin-1-yl-ethanol, in the same manner as Step C in Example 1-D-153, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-morpholin-4-yl-phenyl)-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (1-D-226) as a yellow solid (47.3 mg, 61%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:17])=[C:6]2[C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.[CH:25]([O:28][C:29](Cl)=[O:30])([CH3:27])[CH3:26]>N1C=CC=CC=1>[CH:25]([O:28][C:29](=[O:30])[NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:8]([C:7]=2[F:17])=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)=[CH:23][CH:22]=1)([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc2c(F)c(-c3ccc(N)cc3)n(CC3CC3)c2c1
Solvent: c1ccncc1
Product: CCOc1ccc2c(F)c(-c3ccc(NC(=O)OC(C)C)cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
A mixture of 4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenyl amine (30 mg, 0.093 mmol), pyridine (300 μL), and isopropylchloroformate (1 M in toluene, 110 μL, 0.11 mmol) was stirred at room temperature for 90 minutes. The residue was extracted with a mixture of EtOAc and aqueous HCl. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (CH2Cl2/Hex, 1:1) to provide [4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (35 mg, 92%) as a white solid.
Reaction SMILES: C([N:8]([C@H:16]([CH3:29])[C@@H:17]([OH:28])[CH2:18][C@@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21])CC1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[CH3:29][C@@H:16]([NH2:8])[C@@H:17]([OH:28])[CH2:18][C@@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CC[C@@H](C[C@H](O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@@H](C[C@H](O)[C@@H](C)N)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
N,N-dibenzyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamine (1.46 g, 3.77 mmols) was dissolved in 25 ml of methanol, and 0.43 ml (7.53 mmols) of acetic acid and 0.6 g of 5% palladium on carbon (water content 50%) were added thereto. The reaction solution was stirred under a hydrogen atmosphere at 50° C. for 16 hours. Subsequently, the catalyst was removed by filtration, and the filtrate was concentrated. To the residue were added 15 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted twice with 50 ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was then removed by filtration. The filtrate was concentrated to obtain 0.61 g (2.96 mmols) of (1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamine.
Reaction SMILES: [Br-].Br[CH2:3][C:4]1[CH:5]=[NH+:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:10][C:11]1[N:16]=[C:15]([S:17][CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:14]=[C:13]([OH:18])[CH:12]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1ccc[nH+]c1
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cccnc2)n1
Yield: 38.8 %

Procedure:
A mixture 3-(bromomethyl)pyridin-1-ium bromide (550 mg, 2.5 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (285 mg, 2.0 mmol), and triethylamine (1.1 mL, 8.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solid residue was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The solid product was suspended in acetone (50 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated to dryness. The residue was suspended in water (50 mL). The product was recovered by filtration, washed with diethyl ether (2×20 mL), and dried in vacuo, affording 6-methyl-2-[(pyridin-3-ylmethyl)sulfanyl]pyrimidin-4-ol (181 mg, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.36 (s, 2H), 6.00 (s (br), 1H), 7.32 (td, 1H, J=0.8 Hz, 7.8 Hz), 7.82 (dd, 1H, J=0.8 Hz, 7.8 Hz), 8.42 (dd, 1H, J=0.8 Hz, 4.7 Hz), 8.61 (d, 1H, J=1.8 Hz); M+ 234; HPLC purity: 98.1%.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8]([C:13]2(O)[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[N:9][CH:10]=[CH:11][N:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][C:13]1([C:8]2[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:12][CH:11]=[CH:10][N:9]=2)[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1
Reactant: CCCCCOc1nccnc1C1(O)CN2CCC1CC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCOc1nccnc1C1(Cl)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 30 ml of pentanol that had reacted with 0.5 g of Na (0.022 mol) was added 1.7 g of (7) (0.0071 mol). The reaction was heated to 70° C. for 2 h, the reaction cooled to ambient temperature, and 30 ml of 1 N HCl was added. The excess pentanol was azeotroped off with water and the residue made basic with 5 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% N and then with 10% ethanol-1% NH4OH-CHCl3 to give 1.68 g of 3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol. NMR ppm (CDCl3) 0.97 (3H, t), 1.2 (1H, m), 1.45 (6H, m), 1.87 (2H, m), 2.3 (1H, m), 2.4 (1H, t), 2.8 (1H, m), 2.93 (3H, m), 3.1 (1H, m), 3.98 (1H, s), 4.28 (1H, d), 4.42 (2H, m), 8.01 (1H, d), 8.11 (1H, d). A solution of 1.48 g of this alcohol (0.0051 mol) in 50 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 5 ml of CH2Cl2 was added dropwise. The cooling was removed, the reaction stirred 1.5 h and then heated to reflux for 45 min. After cooling to ambient temperature, ice-water was added to the reaction and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol- 0.5% N4OH-CHCl3 to give 1.27 g of 3-chloro-3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octane. NMR ppm (CDCl3) 0.99 (3H, t), 1.35-1.8 (7H, m), 1.9 (2H, m) 2.37 (1H, m), 2.6-2.82 (2H, m), 3.0 (1H, t), 3.15 (2H, m), 3.6-4.1 (2H, m), 4.42 (2H, t), 8.06 (2H, m). A mixture of 1.05 g of this chloride (0.0034 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated 1 h at 60 psi of H2. The catalyst was filtered off, 25 ml of isopropanolic HCl was added, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 0.28 g of (25), mp 166°-167° C. NMR ppm (CDCl3) 0.95 (3H, t), 1.41 (4H, m), 1.57-1.9 (5H, m), 2.13 (2H, m), 2.45 (1H, m), 3.12 (1H, m), 3.3-4.46 (3H, m), 3.55 (1H, m), 3.7 (1H, m), 4.3 (1H, q), 4.37 (2H, t), 8.03 (1H, d), 8.1 (1H, d). Anal. C16H25N3O-HCl requires C: 61.62; H: 8.40; N: 13.47%. Found C: 61.39; H: 8.07; N: 13.48%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=[N:9]O)[C:6](=O)[CH3:7])[CH3:2].[C:12]([S-:14])#[N:13].[K+]>Cl.O.CCO.[Pd]>[CH2:1]([O:3][C:4]([C:5]1[NH:9][C:12](=[S:14])[NH:13][C:6]=1[CH3:7])=[O:11])[CH3:2]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: N#C[S-]
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c(=S)[nH]c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Pd/C (10%, 1.00 g) is added to a solution of 2-hydroxyimino-3-oxo-butyric acid ethyl ester (62.8 mmol) in HCl (1.25 M in EtOH, 75 mL) and the mixture is stirred at RT under a hydrogen atmosphere (4 bar) for 48 h. After filtration through celite and removal of the solvents crude 2-amino-3-oxo-butyric acid ethyl ester hydrochloride is obtained which is dissolved in a mixture of water (220 mL), EtOH (30 mL) and conc HCl (37%, 2.5 mL). A solution of KSCN (49.9 mmol) in water (25 mL) is added and the mixture is stirred for 2 h at reflux. By cooling in an ice bath the desired product precipitates and is collected by filtration.
Reaction SMILES: C[O-].[Na+].C(OC)=O.[CH3:8][C:9]([S:12]([NH:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)(=[O:14])=[O:13])([CH3:11])[CH3:10].Cl>C1(C)C=CC=CC=1>[CH3:11][C:9]([S:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)(=[O:14])=[O:13])([CH3:8])[CH3:10]
Reactant: COC(=O)[C@H]1CC[C@@H](NS(=O)(=O)C(C)(C)C)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC=O
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)C(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a suspension of powder sodium methylate (7.06 g, 2.5 eq) in toluene (145 mL) was added methyl formate (1.61 mL, 0.5 eq). After the mixture was stirred for an hour at room temperature, (15) (14.5 g, 52.3 mmol) was added to the mixture. The mixture was heated under reflux for 2 hours 25 minutes, cooled and poured into 0.76 mol/L hydrochloric acid (344 mL). The mixture was extracted with ethyl acetate (300 mL×2), and the obtained organic layer was washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain 14.42 g of crystalline residue (cis:trans=3:97). The residue was recrystallized from toluene to obtain (12) (10.2 g, 70% from (15)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:11][N:12]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C=CC=CC=3C2=O)[CH:13]=1.NN.C(Cl)Cl.C(#N)C>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:11]1
Reactant: CC(C)(C)OC(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)cc1-c1ccc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cn(CCCN)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 87 %

Procedure:
The Pthalimido Pyrrole 4 (1 eq) was dissolved in ethanol and hydrazine (3 eq) at room temperature under nitrogen. Upon heating to reflux, the reaction generated a white precipitate. Stir at reflux until complete (−2 h) by TLC(CH2Cl2/acetonitrile (95:5 v/v), the UV active product was at Rf=0.2) and LCMS. Upon reaching completion, the reaction was allowed to cool to room temperature and the precipitate was vacuum-filtered off using a medium to fine cintered-glass filter. The filtrate was concentrated under reduced pressure to a gummy solid. The crude material was taken up in ethanol/EtOAc (1:1 v/v), stirred and the precipitate was filtered off in the same fashion as before. The filtrate was concentrated under reduced pressure and than dried in vacuo for 10-15 min. This process of adding ethanol/EtOAc, filtering and concentrating was done one more time or as needed to remove the majority of the white precipitate and residual hydrazine. The product was then dried in vacuo overnight. The material was used without further purification. Once dried, the reaction yielded the product as a glass (−87% yield over 2 steps).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1(C(N2C=CN=C2)=O)C=CN=C1.O>CN(C)C=O>[N:26]1([CH2:32][CH2:33][NH:34][C:23](=[O:25])[CH2:22][CH2:21][C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C

Procedure:
3-[2-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (Compound VI) (1 g), 630 L of 2-morpholin-4-yl-ethylamine, and 530 mg of di-imidazol-1-yl-methanone, in 10 mL of N,N-dimethyl-formamide, were stirred at room temperature for 1 hr. The reaction mixture was poured into water. The precipitate was filtered and was suspended in hot ethanol. After the suspension was cooled to room temperature, the precipitate was filtered, was washed with ethanol, and was dried in an oven overnight to give N-(2-morpholin-4-yl-ethyl)-3-[2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide (Compound VII).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:21][C:22]([N:16]1[CH:14]2[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15]2)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: c1ccc(CN2CC3CCCC(C2)N3)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCCC1CN(Cc1ccccc1)C2
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of 3-benzyl-3,9-diaza-bicyclo[3.3.1]nonane (755 mg, 3.49 mmol, 1.0 eq) in CH2Cl2 (10 mL) was added di-tert-butylcarbonate (990 mg, 4.54 mmol, 1.3 eq) and triethylamine (0.730 mL, 5.24 mmol, 1.5 eq) and the mixture stirred for 16 hours at 23° C.