Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:17])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:17])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(C2CC2)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C2CC2)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (105 mg, 0.42 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (152 mg, 0.39 mmol) [prepared according to Preparation 6] and PyBrop (246 mg, 0.52 mmol) in Chloroform (6 mL). DIEA (370 μL, 2.19 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 66%): LC-MS (ES) m/z=579 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>N1C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:5]1)=[O:22]
Reactant: CC(C)(C)OC(=O)NCCN1CCNCC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCN1CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from step (i) above (3 g) was dissolved in pyridine (12 ml), 3,4-dichlorobenzoyl chloride (2.05 g) was added and the mixture stirred at room temperature for 18 hours. A solid was collected by filtration and purified by chromatography (dichloromethane:methanol: 0.880 NH4OH, 90:9:1) to give the sub-titled product as an oil (3.59 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 17.1 %

Procedure:
To a mixture of 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.0 mg (0.12 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 8.8 μL (0.069 mMol) 4-chlorobenzoyl chloride. The reaction mixture was mixed for 1 day at ambient temperature. To this mixture were then added 160 mg (0.128 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was diluted with 1.0 mL methanol, treated with potassium carbonate, and filtered through a short column of sodium sulfate. The filtrate was then evaporated to give 2.9 mg (17%) of the title compound as a beige solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([O:26]CC)=O)=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:32][CH2:31]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:42][CH2:41]3)=[O:26])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using Ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.07 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (31 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][CH:12]([F:20])[C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1.OP([O-])(O)=O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:11][CH:12]([F:20])[C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1
Reactant: OCc1ccc(C(F)F)o1
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(C(F)F)o1
Temperature: -60 °C
Yield: 101.4 %

Procedure:
A solution containing 6.5 cm3 of DMSO (dimethyl sulphoxide) and 60 cm3 of methylene chloride is added at -60° C. under a nitrogen atmosphere to a solution containing 3.84 cm3 of oxalyl chloride and 40 cm3 of methylene chloride. The reaction mixture is maintained under agitation at -60° C. and 3.6 g of 5-difluoromethyl 2-furanmethanol in solution in 30 cm3 of methylene chloride is added. Agitation takes place for 2 hours at -60° C. and a solution of 16.1 cm3 of triethylamine and 30 cm3 of methylene chloride is added over 15 minutes. The reaction mixture is maintained under agitation for half an hour at -60° C., then the temperature is allowed to rise to -20° C. and agitation is continued at this temperature for half an hour. It is poured into a solution of sodium acid phosphate, extracted with methylene chloride and dried. 3.6 g of product is obtained which is chromatographed on silica eluting with a hexane--ethyl-acetate mixture 8-2. After chromatography 2.5 g of desired product is obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1>>[CH:2]1(/[CH:1]=[N:8]/[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: O=CC1CC=CCC1
Reactant: NCc1ccccc1
Product: C1=CCC(/C=N/Cc2ccccc2)CC1

Procedure:
In another aspect, a process is described for preparing a compound, or a salt of a compound, or a solvate thereof, of Formula (III). The process comprises steps of: (a) condensing benzylamine with cyclohex-3-enecarbaldehyde to form (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine; (b) contacting (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine with potassium tert-butoxide present in an amount ranging from about 0.05 molar equivalents to about 3.0 molar equivalents of potassium tert-butoxide to (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine to form (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine; (c) contacting (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine with paraformaldehyde present in an amount ranging from about 2.0 molar equivalents to about 5.0 molar equivalents of paraformaldehyde to (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine, in presence of formic acid and a reaction medium to form a compound of Formula (I); (d) contacting a compound of Formula (I) with an a hydrogen halide solution to form an acid addition salt of a compound of Formula (II); (e) contacting aminothiourea and benzoic acid in presence of polyphosphoric acid to form a 2-amino-5-phenyl-1,3,4-thiadiazole phosphate salt; (f) contacting a 2-amino-5-phenyl-1,3,4-thiadiazole salt, CuBr2 and iso-amyl nitrite, in presence of acetonitrile, to form 2-bromo-5-phenyl-1,3,4-thiadiazole; and (g) contacting the acid addition salt of a compound of Formula (II) with 2-bromo-5-phenyl-1,3,4-thiadiazole, in presence of a sodium bis(trimethylsilyl)amide and a reaction medium, to form a reaction mixture, and optionally contacting the reaction mixture with citric acid. In another aspect, the reaction mixture comprises
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17]>C(O)(=O)C>[N:10]1([C:11]2[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([CH:12]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
2,5-dimethoxytetrahydrofuran (0.74 ml, 0.76 g, 5.74 mmol, 1.2 eq) was added to a stirred suspension of dimethyl 5-aminoisophthalate (1.0 g, 4.78 mmol, 1 eq) in 7 ml acetic acid under Ar. The mixture was heated to reflux at 135° C. After 45 min the reaction was cooled to RT, and the solvent was removed in vacuo. The residue was stirred in saturated aqueous NaHCO3/EtOAc overnight. The layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (×1), water (×2), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.288 g (1.11 mmol, 23% yield) of the product. A significant amount of crude product was also collected.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C@@H:8]1[C@H:16]([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]1[C:18](=[O:23])[C@@H:19]([NH2:22])[CH2:20][CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:24](NC([C@H]1[C@@H](C)C2C(=CC=CC=2)N1C(=O)[C@@H](N)CC)=O)CCC>>[CH2:1]([NH:5][C:6]([CH:8]1[C:16]([CH3:24])([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]1[C:18](=[O:23])[C@@H:19]([NH2:22])[CH2:20][CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H]1[C@H](C)c2ccccc2N1C(=O)[C@@H](N)CC
Reactant: CCCCNC(=O)[C@H]1[C@@H](C)c2ccccc2N1C(=O)[C@@H](N)CC
Product: CCCCNC(=O)C1N(C(=O)[C@@H](N)CC)c2ccccc2C1(C)C

Procedure:
1-(2(S)-aminobutyryl)-3(R)-methylindoline-2(S)-carboxylic acid butylamide and 1-(2(S)-aminobutyryl)-3(S)-methylindoline-2(R)-carboxylic acid butylamide;
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[OH:45].N12CCCN=C1CCCCC2>CS(C)=O>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1O
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Nc4ccccc4O)nc32)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 8 %

Procedure:
A mixture of 1-[2-chloro6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide (0.20 g, 0.38 mmol), 2-aminophenol (0.20 g, 1.83 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 ml, DBU) and dimethylsulphoxide (1 ml) was stirred and heated at 140° C. under nitrogen for 6h, and then left at 21° C. overnight. The mixture was partitioned between ethyl acetate (200 ml) and water (40 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the total organic solution was washed (water, 20 ml), dried (Na2SO4) and evaporated. The residue was purified on flash silica eluting with dichloromethane:methanol (19:1), and then by preparative TLC (20×20 cm plate with 2 mm layer of Kieselgel 60 F254 ; Art 5717) in dichloromethane:ethyl acetate:ethanol 9:9:2, and then by preparative HPLC (30 to 70% acetonitrile) to give the title compound (0.018 g) as a cream foam, MH+ =596. Analysis found: C,52.2, H,4.3, N,11.8; C32H33N7O5.2CF3CO2H requires C,52.5, H,4.3, N,11.9%.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.C(O)(=O)C.[N:34]([O-])=O.[Na+]>O>[ClH:1].[OH:29][CH:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][O:12][C:6]1[C:5]2[N:4]=[N:34][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(CCNCC(O)COc2cccc(N)c2N)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CCNCC(O)COc2cccc3[nH]nnc23)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
14.1 g. 2,3-Diamino-1-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)-propoxy]-benzene trihydrochloride are dissolved in 10 ml. water and 3.5 ml. glacial acetic acid, cooled to 5° C. and mixed with 2.07 g. sodium nitrite in 3.6 ml. water. The reaction mixture is then stirred for 2.5 hours at ambient temperature. The resultant sodium chloride is precipitated out by the addition of 480 ml. isopropanol. After filtration, the filtrate is evaporated, purified over a column of silica gel using methanol/ethyl acetate (2:1 v/v) as elution agent, mixed with ethereal hydrochloric acid and the hydrochloride so obtained is crystallized from ethanol. There are obtained 1.26 g. (10% of theory) 4-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)-propoxy]-benzotriazole hydrochloride; m.p. 123°-124° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>ClCCCl>[C:12]1([NH:11][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 4-necked RBF equipped with an overhead stirrer, J-Kem internal temperature probe, a reflux condenser and an addition funnel was placed isonicotinoyl chloride-hydrochloride (50 g, 0.28 mol). To this solid was added 500 ml of 1,2-dichloroethane and the slurry cooled to 0° C. using an ice/water bath. To the addition funnel was added a mixture of the aniline (31.4 g, 0.34 mol) and Et3N (59.5 g, 0.59 mol) in 50 ml of 1,2-dichloroethane. This mixture was slowly added to the slurry over 25 min. A slight exotherm was observed from 2.4° C. to 15° C. after the addition of the first 10 ml. The reaction mixture was observed to cool down slowly. The reaction mixture turned yellow and became heterogeneous. After 30 min., the ice bath was removed and the reaction heated to reflux for 1.5 h. Deionized water, 100 ml, was added and an off-white precipitate formed. The precipitate was collected by filtering through paper on a Buchner funnel and placed in a drying oven (60° C.) overnight to give 45 g (81% th) of an off-white crystalline solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2O)[N:11]=1)(=[O:8])[CH3:7].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:6]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[Cl:3])[N:11]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccc2c(O)ccnc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(=O)Nc1ccc2c(Cl)ccnc2n1
Yield: 18 %

Procedure:
Phosphorous oxychloride (6.0 ml) was added to a stirred mixture of 2-acetamido-5-hydroxy-1,8-naphthyridine (2.4 g, 11.8 mmol) and N,N-dimethylaniline (6.0 ml) in toluene (100 ml). The mixture was then heated at reflux for 1 hour. The mixture was allowed to cool, the tolulene was removed by evaporation and the residue was partitioned between methylene chloride and aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried (MgSO4) and the solvent was removed by evaporation to give 2-acetamido-5-chloro-1,8-naphthyridine (470 mg, 18%) as a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].O1CCCC1.CC(C)([O-])C.[K+:20].[C:21](=[S:23])=[S:22]>CCOCC>[O:1]([CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[C:21]([S-:23])=[S:22].[K+:20]
Reactant: S=C=S
Reactant: O=C1CCCN1CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCCN1CCOC(=S)[S-]
Reaction time: 1 h

Procedure:
To a stirred solution of 5.16 g. of N-(2-hydroxyethyl)-2-oxo-pyrrolidine in 200 ml. of anhydrous tetrahydrofuran at room temperature was added 4.48 g. of potassium t-butoxide. A gummy precipitate formed. The mixture was stirred for 1 hour, and then 3.6 ml. of carbon disulfide was added. The mixture was stirred for 2 hours, and then 100 ml. of anhydrous ether was added, causing the formation of a gummy precipitate. The solvent was decanted from the gummy precipitate, and the gummy precipitate was dried under high vacuum to give a foam (5.0 g.) of the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[C:22]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31](O)=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:31]([C@@H:30]3[CH2:34][CH2:35][CH2:36][N:29]3[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[NH:21][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2[nH]1
Temperature: 85 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
EDCI.HCl (16.9 g, 88.0 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine (15.0 g, 80.0 mmol), N-Boc-L-proline (18.13 g, 84.0 mmol) and 1-hydroxybenzotriazole (12.28 g, 80.0 mmol) in CH2Cl2 (500 mL) and stirred at ambient conditions for 16 h. The mixture was then diluted with water. The resulting white precipitate was filtered away and the layers were separated. The organic layer was washed with water, dried (brine; Na2SO4), filtered and concentrated in vacuo to provide a brown foam. Acetic acid (300 mL) was added to the foam and the mixture was heated at 85° C. (bath temperature) for 5 h. The volatile component was removed in vacuo and the residue was dissolved in EtOAc, washed with water and the organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; 0-37% EtOAc/CH2Cl2). The partially pure material was re-submitted to flash chromatography (silica gel; 20-35% EtOAc/CH2Cl2) to provide (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (17.98 g, 61.2% yield) as yellow foam. LC-MS retention time 1.23 min; calcd. for C16H20BrN3O2: 365.07. found m/z 368.07 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.59-7.75 (m., 1H), 7.38-7.53 (m, 1H), 7.31-7.38 (m, 1H), 5.04-5.09 (m, 0.3H), 4.94-5.00 (m, 0.7H), 3.68-3.76 (m, 1H), 3.50-3.59 (m, 1H), 2.34-2.51 (m., 1H), 1.95-2.12 (m., 3H), 1.47 (br s, 3H), 1.15 (s, 6H).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:7][C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].[ClH:20]>C1COCC1.CO>[ClH:20].[ClH:20].[NH2:5][CH:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=C(N)c1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(N)c1cccnc1
Temperature: -2.5 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
Glacial acetic acid (526.9 g, 8.78 mol) was added dropwise at <−5° C. to a suspension of methyl 3-amino-3-(3-pyridyl)-2-propenoate (0.45 mol) and sodium borohydride (44.3 g, 1.17 mol) in THF (500 g) and the resulting reaction mixture was stirred at −5-0° C. After 5 h, methanol (600 g) was added dropwise to the solution at −5-0° C. After 0.5 hours, HCl (163 g, 4.47 mol) was bubbled through the solution and stirred at 0° C. After 8 h, the white precipitate was filtered off and dried at 40° C. to yield 101.6 g (89%) of methyl 3-Amino-3-(3-pyridyl)propanoate dihydrochloride.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:7]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:6]=1)=[O:4].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl:31]CCl>Cl>[Cl-:31].[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:7]1[CH:6]=[C:5]([CH:15]=[CH:14][C:8]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:3]([CH2:2][N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1Oc1ccc(F)cc1F
Reactant: ClCCl
Reactant: c1ccncc1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)C[n+]2ccccc2)cc1Oc1ccc(F)cc1F
Product: [Cl-]

Procedure:
A solution of 4'-bromoacetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide (2.5 g) and pyridine (526 mg) in dichloromethane (20 ml) was refluxed for 4 hours. The mixture was concentrated, and the residue was dissolved in water and washed with ethyl acetate. To the aqueous layer was added sodium bicarbonate, giving an amorphous powder. The powder 0.76 g) was dissolved in an ethanolic solution of hydrogen chloride. The residue obtained by evaporation of the solution was crystallized with ethyl acetate to give a powder of 1-[3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzoylmethyl]pyridinium chloride (0.75 g).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[K+].[Br-]>CCOCC>[Cl-:9].[C:16]([O:8][CH:1]([N+:13]1[CH:14]=[CH:15][N:11]([CH3:10])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1ccnc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: Cn1cc[n+](C(OC(=O)c2ccccc2)c2ccccc2)c1
Product: [Cl-]

Procedure:
To an ether solution of benzoyl chloride 2.81 g (0.02 mol) there was added dropwise 1.67 g (0.02 mol) 1-methylimidazole with stirring. The resulting mixture was evaporated in vacuo and the residue was allowed to react with 2.12 g (0.02 mol) benzaldehyde at 70° overnite. After cooling, the reaction mixture was triturated with ether and was solid separated by filtration. Recrystallization from dichloromethane:dioxane gave 4.2 g (0.012 mol), 65%, 9, mp 199°-201°; ir (KBr) 1740 cm-1 ; pmr (CDCl3) δ 4.17 (s, 3H), 8.18-7.25 (m, 12H), 8.50 (s, 1H) and 11.1 (bs, 1H) ppm.