Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:3]=1.FC(F)(F)C(O)=O.[NH2:33][CH2:34][CH2:35][NH:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:4]1[N:3]=[C:2]([NH:33][CH2:34][CH2:35][NH:36][C:37]2[N:38]=[CH:39][C:40]([C:41]#[N:42])=[CH:43][CH:44]=2)[N:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nc(CN4CCOCC4)nn3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCN)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(CN4CCOCC4)nn23)nc1

Procedure:
100 mg (0.25 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(morpholin-4-ylmethyl)[1,2,4]-triazolo[1,5-c]pyrimidine (Example 150A) and 60 mg (0.30 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (Example 13A) are introduced into DMSO (4 ml), 0.26 ml (1.5 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 140° C. for 45 min. The reaction mixture is purified by preparative HPLC. 62 mg (46% of theory) of the product are obtained as a solid.
Reaction SMILES: C([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:36][CH2:35]4)=[C:26]([CH3:46])[CH:25]=3)=[O:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:47])C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH3:43][C:42]([CH3:45])([CH3:44])[CH2:41][CH2:40][N:37]1[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]([N:14]3[CH2:13][CH2:12][C:11]4[N:10]=[C:9]([CH3:47])[NH:8][C:17]=4[C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]3=4)=[O:23])=[CH:25][C:26]=2[CH3:46])[CH2:39][CH2:38]1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCN(CCC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(C)c1)CC2
Yield: 20 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-methyl-phenyl)-methanone from Example E70.3 (98 mg, 0.15 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and hydrogenated over 20 wt. % palladium hydroxide catalyst (98 mg) for 8 h. The mixture was filtered through glass-fibre paper and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (17 mg, 20%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][CH2:20][CH2:19][CH2:18][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCCN1CCCC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1ccc2c(NCCCN3CCCC3)ccnc2c1

Procedure:
3.08 g from 7.72 g of 4,7-dichloroquinoline and 5 g of 3-(pyrrolidin-1-yl)-propylamine (reaction duration 16 hours at 140° C.); the base was converted with isopropanolic hydrochloric acid into the dihydrochloride which when recrystallized from acetonitrile/ethanol, yielded colourless crystals, m.p.: 204°-206° C.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].CI>CCCCCC.O1CCCC1>[F:6][C:7]1[C:8]([F:15])=[CH:9][C:10]([F:14])=[C:11]([F:13])[C:12]=1[CH3:1]
Reactant: Fc1cc(F)c(F)cc1F
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(F)c(F)cc(F)c1F
Temperature: -60 °C
Reaction time: 2 h

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 62.5 ml) was added dropwise to a well stirred solution of 1,2,4,5-tetrafluorobenzene (15.0 g) in dry tetrahydrofuran (150 ml) maintained at a temperature of -60° C. under an atmosphere of dry argon. When the addition was complete the mixture was stirred at -45° C. for 2 hours and then methyl iodide (14.2 g) was added dropwise whilst the temperature was kept at -45° C. After a period of 30 minutes the mixture was allowed to warm to the ambient temperature, poured into distilled water and the mixture extracted with diethyl ether (2×50 ml), and the extracts dried over anhydrous magnesium sulphate. After filtering the solution was concentrated by evaporation of the solvents at atmospheric pressure. The residual oil was distilled and the fraction boiling in the range 115°-122° C. at atmospheric pressure (6.2 g) collected, identified by n.m.r. and gas chromatographic analysis as consisting of ca. 95% of the required 2,3,5,6-tetrafluorotoluene and ca. 5% of 2,3,5,6-tetrafluoro-1,4-xylene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([F:13])[CH:3]=1.[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C.Cl>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][C:4]=1[F:13])[CH2:10][CH2:11][CH3:12]
Reactant: COB(OC)OC
Reactant: CCCCOc1ccc(Br)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(B(O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
The compound (T-8) (97.5 g) obtained in the above procedure was dissolved in dried THF (500 ml) and the solution was cooled to −70° C. n-BuLi (241 ml) was added dropwise under an atmosphere of nitrogen, and the stirring was continued at −70° C. for another 2 hours. Then, trimethyl borate (62.4 g) in a dried THF solution was added dropwise slowly at −70° C., and the mixture was warmed up to room temperature. The stirring was continued for another 16 hours. After the completion of the reaction, 2N—HCl (200 ml) was added to the reaction mixture. The mixture was extracted with toluene, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave pale brown solids. Recrystallization (heptane:toluene=4:1 by volume) gave the compound (T-9) as colorless powders (54.8 g) in 66% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1>>[Cl:14][C:15]1[N:16]=[C:17]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[CH:18]=[N:19][CH:20]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: Clc1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Yield: 36.9 %

Procedure:
In a procedure analogous to example 1, reaction of 4-morpholinoaniline (2.15 g, 12.1 mmol) and 2,6-dichloropyrazine (0.756 g, 5.03 mmol) furnished the product (0.54 g, 37%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[Na+].[CH3:12][S:13]([O-:15])=[O:14]>CN(C=O)C>[CH3:12][S:13]([CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1)(=[O:15])=[O:14]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(=O)[nH]c(=O)[nH]1
Temperature: 125 °C
Yield: 112.3 %

Procedure:
6-(Chloromethyl)-1H-pyrimidine-2,4-dione (175 g, 1.09 mol) was dissolved in DMF (2 L) and methanesulphinic acid sodium salt (133.5 g, 1.31 mol) was added. The reaction was heated to 125° C. for 2 hours then allowed to cool and the suspension filtered and concentrated in vacuo to give a yellow solid. The crude material was washed with water, filtered, then triturated with toluene. The solid was filtered then triturated with isohexane to leave the desired compound as a yellow solid (250 g). The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16]C)=[O:14].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[C:3]([OH:11])=[C:4]([C:8]([C:9]2[CH2:16][O:15][C:13](=[O:14])[C:12]=2[OH:18])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(F)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OCC(C(=O)c2cccc(F)c2O)=C1O
Yield: 40.3 %

Procedure:
A solution of 1-(3-fluoro-2-hydroxyphenyl) ethanone (30 g) and diethyl oxalate (31 g) in ethanol (600 mls) was added dropwise to sodium ethoxide (from 9.85 g of sodium) in ethanol (600 mls) and the mixture was stirred and heated at reflux for 2 days. The mixture was cooled, diluted with 60-80 petrol and the solid was collected and dried. A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours. The solid was filtered out, the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum. The aqueous solution was acidified to pH3, the precipitate was collected, washed with water and recrystallised from acetone/water to give the title compound as yellow needles (18.7 g). M.p. 194°-208° (decomp), i.r. λmax (nujol) 1768, 1642 cm-1 (C=O).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19](C)(C)C)[C:9]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:8]=2[N:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[C:28]([C:26]1[CH:25]=[CH:24][C:9]2[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:23])[CH3:19])[C:6]([CH2:5][OH:4])=[N:7][C:8]=2[CH:27]=1)#[N:29]
Reactant: CC(=O)OCc1nc2cc(C#N)ccc2n1CCCCCCOC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OCCCCCCn1c(CO)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of 2,2-Dimethyl-propionic acid 6-(2-acetoxymethyl-5-cyano-benzoimidazol-1-yl)-hexyl ester (7.2 g, 18 mmol) and K2CO3 (14 g, 101 mmol) in MeOH (100 mL) was stirred at the ambient temperature for 4 h. The nixture was diluted with EtOAc (100 mL) and filtered. The filtrate was evaporated. The residue was dissolved in EtOAc (300 mL) and washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was left for 2 weeks before being purified by flash chromatography (hexanes:acetone 1:1) to give 4.1 g (72%) of acetic acid 6-(5-cyano-2-hydroxymethyl-benzoimidazol-1-yl)-hexyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9](OCC)=[O:10]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:15][C:9](=[O:10])[CH2:8][O:7][C:6]=2[CH:14]=1
Reactant: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1COc2cc(F)ccc2N1
Temperature: 80 °C
Yield: 62.6 %

Procedure:
Iron powder (36.42 g) was suspended in 5% aqueous acetic acid (69 ml) and heated to 80° C. To the suspension, a solution of ethyl 5-fluoro-2-nitrophenoxyacetate (15.86 g) in acetic acid (65 ml) and ethyl acetate (65 ml) was dropwise added, and the resultant mixture was heated at 60° to 80° C. under reflux for 3 hours. After removal of residue by filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 7-fluoro-2H-1,4-benzoxazin-3(4H)-one (6.82 g). m.p., 186.720 C. 1H-NMR (CDCl3 +DMSO-D6) δ ppm: 4.2 (1H, broad), 4.51 (2H, s), 6.5-7.0 (3H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[C:8](=[O:15])[N:9]2[C:13]=1[CH2:12][CH2:11][CH:10]2[CH3:14])=[O:4].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=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.CCO>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:7]1[C:8](=[O:15])[N:9]2[C:13](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[CH2:12][CH2:11][CH:10]2[CH3:14]
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(=O)n2c1CCC2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1CCc2c(C(=O)O)cc(-c3ccccc3F)c(=O)n21
Yield: 53.6 %

Procedure:
To a microwave tube was added methyl-3-methyl-5-oxo-6-(trifluoromethylsulfonyloxy)-1,2,3,5-tetrahydroindolizine-8-carboxylate (94 mg, 0.26 mmol), 2-fluorophenylboronic acid (37 mg, 0.26 mmol, Aldrich), and 2 M sodium carbonate (0.65 mL, 1.30 mmol). To this was added 4 mL of toluene, 0.25 mL of EtOH, and Pd(PPh3)4 (20 mg, 0.17 mmol, Aldrich). The tube was sealed and treated in Emry's optimizer for 15 min at 160° C. The aqueous phase was separated and acidified to pH 2 with 2 N HCl and extracted with EtOAc (3×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 40 mg (53%) of the title compound as a light brown residue. MS m/z: 288.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH2:14])[CH2:6]2.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6]2
Reactant: O=C1CCCC1
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)[C@@H](CNC1CCCC1)C2
Reaction time: 4 h

Procedure:
At ambient temperature, 2.9 g (15 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine and 1.3 mL (15 mmol/1 eq.) of cyclopentanone are mixed into 60 mL of dichloromethane. There are then added 4.8 g (22.5 mmol/1.5 eq.) of sodium triacetoxyborohydride and then 0.86 mL (15 mmol/1 eq.) of acetic acid, and stirring is carried out at ambient temperature for 4 hours. 90 mL of 1N sodium hydroxide solution are then poured in; extraction with two 120 mL quantities of ether is then carried out. The combined organic phases are washed with 90 mL of water and then with 90 mL of saturated aqueous sodium chloride solution and are then dried over magnesium sulphate. After filtration and concentration, the desired product is collected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCC1
Yield: 52.5 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with cyclopentanecarbonyl chloride (0.50 mL, 4.1 mmol) to provide 0.71 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanecarboxamide as a white solid, m.p. 168.6-169.8° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.ON1C2C=CC=CC=2N=N1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][CH2:29][NH2:30].Cl.CN(C)CCCN=C=NCC>C(#N)C>[NH2:1][C:2]1[C:3]([C:9]([NH:30][CH2:29][CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NCCc1cccs1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)NCCc1cccs1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 3-amino-6-bromopyrazine-2-carboxylic acid (0.50 g, 2.3 mmol; described in: Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 2798-2800), 1-hydroxybenzotriazole hydrate (0.41 g, 2.7 mmol) in acetonitrile (5 mL) were added to a stirred solution of 2-thien-2-ylethanamine (0.32 g, 2.5 mmol) in acetonitrile (5 mL) followed by addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.52 g, 2.7 mmol) and acetonitrile (1.5 mL). The resulting mixture was stirred at room temperature over night and the solvent was evaporated. The residue was re-crystallized from acetonitrile and subsequently from methanol to give 0.5 g (66% yield) of the title compound: 1H NMR DMSO-d6, 400 MHz) δ 8.73 (t, J=6 Hz, 1H), 8.34 (s, 1H), 7.71 (br s, 2H), 7.34 (dd, J=5, 1 Hz, 1H), 6.95 (d, J=3 Hz, 1H), 6.91 (m, 1H), 3.50 (q, J=7 Hz, 2H), 3.05 (t, J=7 Hz, 2H); MS (ES) m/z 327 and 329 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C1OCCOCCOCCOCCOCCOC1.[H-].[Na+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(OCC)(=O)C.ClCCl.O1CCCC1>[CH2:41]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: CCOP(=O)(CCCCCCCCCCCO)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCCCCCCCCOCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
Diethyl 11-hydroxyundecylphosphonate (4.0 g, 13.0 mmol) and 18-crown-6 (spatula tip) were added to anhydrous tetrahydrofuran under inert atmosphere. Sodium hydride (312 mg, 13.0 mmol) was added and the solution allowed to stir for 10 minutes. Benzyl bromide (2.4 mL, 19.5 mmol) was then added and the reaction stirred at reflux for 4 hours. After cooling to room temperature, dichloromethane was added and the mixture washed with water and brine. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure to yield a liquid. Column chromatography (stationary phase:silica, mobile phase:ethyl acetate) was used to isolate the desired product (Rf=0.70, ethyl acetate) as a clear oil (2.173 g, 42% yield). 1H NMR (500.13 MHz, CD2Cl2) δ 7.36-7.29 (m, 4H), 7.29-7.23 (m), 4.47 (2H), 4.10-3.97 (m, 4H), 3.45 (t, J=6.62 Hz, 2H), 1.72-1.62 (m, 2H), 1.62-1.48 (m, 4H), 1.40-1.20 (m, 20H). 13C{1H} NMR (100.62 MHz, CD2Cl2) δ 139.4, 128.6 (2C), 127.9 (2C), 127.7, 73.03, 70.88, 61.57 (d, J=6.4 Hz, 2C), 30.95 (d, J=16.8 Hz), 30.17, 29.94, 29.91, 29.85, 29.75, 29.48, 26.58, 25.91 (d, J=139.8 Hz), 22.78 (d, J=5.3 Hz), 16.68 (d, J=5.9 Hz, 2C). 31P{1H} NMR (202.45 MHz, CD2Cl2): δ 32.83. Analysis calculated (found) %: C 66.30 (65.66), H 9.86 (9.95). MS (ESI, m/z): 399 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 399.2659 (399.2671).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17](C#N)[S:18]([N:21]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:15]=2)[C:10]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[CH3:44])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][S:18]([N:21]([CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH3:22])(=[O:19])=[O:20])=[CH:14][CH:15]=2)[C:10]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[CH3:44])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(C(C#N)S(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(CS(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
To a stirred solution of 1-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (d), 11.61 g, 19.3 mmol) in ethanol (35 ml) at ambient temperature was added 2N potassium hydroxide solution (35 ml, 70 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hr. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3×100 ml). The organic extracts were combined and evaporated in vacuo to yield the crude product as a dark brown oil. The oil was diluted with ethanol (35 ml) and stirred at ambient temperature for 12 hr, which resulted in precipitation. The mixture was then filtered and the solid dried in vacuo at 50° C. overnight to yield the title compound (6.82 g, 61%) as a beige solid. m.p. 117-120° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([N+:19]([O-])=O)=[CH:13][C:12]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CO.[Zn]>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:8]([CH2:9][CH2:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[CH:13][C:12]=3[Cl:22])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:25][CH:26]=2)[CH2:31][CH2:32]1)=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1N
Temperature: 75 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 4-(4-((tert-butoxycarbonyl (2-chloro-5-methoxy-4-nitrophenethyl)amino)methyl)phenyl)piperazine-1-carboxylate (0.480 g, 0.793 mmol) in methanol (15 mL), a saturated solution of NH4Cl (10 mL) and zinc powder (0.257 g, 3.96 mmol) were added at room temperature and the reaction stirred at 70-80° C. for 1 hour. The mixture was allowed to cool to room temperature and filtered through a celite pad. Water (40 mL) was added to the filtrate and the mixture extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (0.440 g, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[N+:15]([O-])=O)[CH3:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[NH2:15])[CH3:2]
Reactant: CCOC(=O)c1cc(SCC)cc(N)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(SCC)cc(N)c1N

Procedure:
1.5 g (5.5 mmol) of 3-amino-5-ethylsulfanyl-2-nitro-benzoic acid ethyl ester was reduced by 2.9 g (16.6 mmol) of Na2S2O4 in 28 mL of ethanol/ethyl acetate/water (3:3:1) at 80° C. for 3 h to produce 2,3-diamino-5-ethylsulfanyl-benzoic acid ethyl ester. LCMS: 241 (M+1)+.