Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([O:9][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: C=C(C)C
Reactant: CC(C)(Br)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Br

Procedure:
Isobutene is condensed into a solution of 2-bromo-2-methylpropanoic acid (10 mmol) and trifluoroacetic acid (1 mmol) in 100 mL of CH2Cl2 until the starting material is consumed, as observed by TLC. The volatile components are evaporated in vacuo, and the residue is filtered through a pad of neutral alumina using 50% ether/hexane. The filtrate is concentrated in vacuo and used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[C:18]([Br:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:9])([CH3:6])[CH3:5].Cl>C1COCC1.[OH-].[Na+].CO>[Br:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[O:9])[CH:19]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1cc(Br)c2ccccc2c1OCCOc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1cc(Br)c2ccccc2c1OCCOc1ccc(F)cc1)C(=O)O

Procedure:
61 mg 2-({4-bromo-1-[2-(4-fluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester in 0.5 ml THF, 0.36 ml of 2 M sodium hydroxide and 1.7 ml methanol were reacted in a microwave at 120° C. for 6 min. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated. After purification of the residue by RP-HPLC 27 mg of 2-({4-bromo-1-[2-(4-fluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:17]1([N:23]2[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:27]4[N:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:24]=[N:25][N:26]=4)[CH2:29][CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)O)c[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.3 g, 10.0 mmol) was dissolved in DMF (66 mL) and treated with 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.31 g, 10.0 mmol), triethylamine (2.8 mL, 20.0 mmol) and TBTU (3.5 g, 11.0 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A white solid precipitated out and it was collected by filtration and recrystallized with MeOH to afford the title compound (2.4 g) as a yellow solid. 1HNMR (500 MHz, DMSO-D6) δ 8.53 (s, 1H), 7.81 (d, J=4.0 Hz; 1H), 7.75-7.54 (m, 5H), 3.69 (m, 2H), 3.44 (m, 2H), 3.33 (m, 2H), 3.17 (m, 2H). LCMS: m/e 436 (M+H)+, ret time 1.73 min (method 2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].Br[CH2:11][C:12]([O:14][CH2:15]C)=[O:13].O>O1CCOCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: NCc1ccccc1N
Reactant: CCOC(=O)CBr
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CNCc1ccccc1N
Temperature: 25 °C

Procedure:
2-Aminomethyl-phenylamine (1.54 g, 10.1 mmol) and TEA (3.06 ml, 20.2 mmol) are refluxed in 1,4-dioxane. A solution of ethyl bromoacetate (1.12 ml, 10.1 mmol) in 1,4-dioxane (5 ml) is added slowly over 1 hour resulting in a precipitate. The reaction mixture is stirred at reflux for 2 hours. The reaction mixture is cooled to RT, treated with water and extracted with EtOAc, the organic phase is dried over MgSO4, filtered and is concentrated in vacuo. Purification by flash column chromatography on silica, eluting with DCM:MeOH (40:1) affords the title compound; [M+H]+ 195.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>O>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(NCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-fluoroaniline (4.7 ml, 50 mmol), benzaldehyde (5.3 g, 50 mmol) and one crystal p-toluene-sulfonic acid is refluxed using a Dean-Stark® apparatus until no more water is collected and the mixture is concentrated in vacuo. The crude product is dissolved in 100 ml 96% ethanol and added sodium borohydride (4.0 g, 100 mmol) and stirred for 1 hour. Most of the ethanol is removed in vacuo and the residue is taken up in water and 15 g of potassium hydroxide in 50 ml water is added, causing the amine to crystallize. The product is recrystallized from methanol/water (in a ratio of 4 to 1) yielding the title compound as white crystals. Mp 38°-39° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1([C:24]#N)[CH2:8][CH2:7][CH:6]([CH:9]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.[C:27]1([Mg]Cl)[CH:32]=[CH:31]C=[CH:29][CH:28]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:22]([O:21][CH:19]([O:18][CH:9]([CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:26])[CH3:1])([C:24]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[CH2:4][CH2:5]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:20])[CH3:23]
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOC(C)OC(COc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OC(COc1ccccc1)C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanecarbonitrile (871 mg, 2.4 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise to a 2 M solution of phenylmagnesium chloride in tetrahydrofuran (3.6 ml, 7.3 mmol), while cooling with ice. The mixture was stirred at room temperature overnight and saturated ammonium chloride solution and water (5 ml of each) were then added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].C(=O)([O-])[O-].[Cs+].[Cs+].[N:26]1([C:32]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.COCCOC>O.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>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:37]4[CH:36]=[CH:35][C:34]([C:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:33])=[CH:39][CH:38]=4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Temperature: 85 °C
Yield: 13.3 %

Procedure:
A sealable tube was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 0.200 g, 0.518 mmol), cesium carbonate (0.253 g, 0.777 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.183 g, 0.777 mmol) and DME (2 mL). The mixture was degassed under nitrogen for 10 minutes and Pd(PPh3)4 (0.0299 g, 0.0259 mmol) was added as a solid. The mixture was heated to 85° C. for 18 hours. The crude was diluted with water (300 mL), extracted with EtOAc/MeOH (4:1, 2×300 mL), dried organic over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (2.0 mm thickness) eluting with EtOAc/MeOH (9:1) to give product (31 mg, 12%) as a white solid. LRMS (APCI+) 450 m/z (M+1) detected.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].Cl>ClCCl>[Cl:28][CH2:29][C:30]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:31]
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dissolve 5-(3-methylaminopropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (7.0 g, 0.026 mol) and triethylamine (4 mL) in dichloromethane (100 mL) and cool with an ice-bath. Add, by dropwise addition, a solution of chloroacetyl chloride (3.23 g, 0.0286 mol) in dichloromethane (25 mL). Stir at room temperature for 12 hours, shake with dilute hydrochloric acid and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.ClC1C=CC2N=CCN=C(C3C=CC=CC=3)C=2C=1.C(O)(=O)C.[SH:41][CH2:42][CH2:43][OH:44]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([S:41][CH2:42][CH2:43][OH:44])[CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1
Reactant: OCCS
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCCN2
Agent: Clc1ccc2c(c1)C(c1ccccc1)=NCC=N2
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCCSC1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine (10 g) was oxidized to 7-chloro-5-phenyl-3H-1,4-benzodiazepine as described in Example 1 with the addition of 0.1 ml of acetic acid. The crude oxidation product was taken up in THF (60 ml), treated with 2-mercaptoethanol (10 ml ) and heated under reflux overnight. The resulting solution was concentrated under reduced pressure until the product began to crystallize and then diluted with 100 ml of ether. The product was collected and washed with ether to give the above-named product as colorless crystals, mp 135°-140° (dec).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8].[I-:19].[Na+].C(OC)(C)(C)C>CC(C)=O>[I:19][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Cc1oc(-c2ccc3ccccc3c2)nc1CI

Procedure:
1.8 g of 4-chloromethyl-5-methyl-2-naphthalen-2-yloxazole and 3 g of sodium iodide in 150 ml of acetone are heated under reflux for 2 hours. After the reaction mixture has been cooled, 300 ml of methyl tert-butyl ether are added, the mixture is washed three times with saturated Na2S2O3 solution and dried over MgSO4 and the solvents are then removed under reduced pressure. This gives 2.7 g of 4-iodomethyl-5-methyl-2-naphthalen-2-yloxazole as a light-yellow solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=O.Cl>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:10]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:12][C:11]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: COC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
Methyl thioglycolate (19.62 mL, 0.216 mol) was added dropwise, via syringe pump, to a stirred suspension of 95% sodium hydride (5.99 g, 0.237 mol) in dry N,N-dimethyl-formamide (400 mL) at r.t. under nitrogen (CAUTION: hydrogen evolution). Upon complete addition, the reaction was stirred for 10 min and then a solution of 2-chloro-5-nitrobenzaldehyde (40.0 g, 0.216 mol) in DMF (120 mL) was added. The solution turned orange and a gentle exotherm was observed. After 1 h, the now yellow mixture was heated to 100° C. for 5 h. The mixture turned amber in appearance. After cooling to r.t. the mixture was poured into 1 N aqueous hydrochloric acid (500 mL). The resulting yellow precipitate was filtered off and washed with water (250 mL). The solid was suspended in hot methanol/ethyl acetate (1:1) (1000 mL) and allowed to cool to r.t. The resulting solid was filtered off and air dried to yield methyl 5-nitrobenzo[b]thiophene-2-carboxylate (33.77 g, 66%) as a tan amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 3.92 (s, 3 H), 8.32 (dd, J=9, 2 Hz, 1 H), 8.37 (d, J=9 Hz, 1 H), 8.45 (s, 1 H), 9.00 (d, J=2 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[C:11]=1[F:12].[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([S:10][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)[NH:7][C:6]=2[C:11]=1[F:12]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Fc1ccc2nc(S)[nH]c2c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ccc(F)c(F)c3[nH]2)o1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
6,7-Difluoro-1H-benzimidazole-2-thiol (0.34 g, 1.81 mmol) is suspended into 20 mL of tetrahydrofuran (THF) under argon. Then, 130 mg (2.71 mmol) of sodium hydride are added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.25 g, 1.81 mmol) is then added and the reaction mixture is stirred at room temperature for 3 h, upon which it is poured on ice and extracted twice with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 70 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/THF from 100/0 to 80/20 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 30 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol from 100/0 to 95/5 v/v; rate: 20 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 0.28 g of 5-(6,7-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow meringue. LCMS-DAD-ELSD: 281(+): [M+H]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](=[O:21])[CH2:13][CH:14]2CC(O)=O)=[CH:10][CH:9]=1>ClCCl>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](=[O:21])[CH2:13][CH:14]2[CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC1CC(=O)c2ccc(F)cc21
Solvent: ClCCl
Product: O=C(Cl)CC1CC(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Oxalyl chloride (4.5 g, 0.035 mol, Aldrich) was added to an ice cold stirring mixture of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid (5.0 g, 0.024 mol) in dichloromethane (200 ml) under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirring was continued for 48 hrs. The volatiles were removed from the solution by spin evaporation in vacuo with the addition of dichloromethane (3×50 ml) to give 2-(6-fluoro-3-oxo-1-indanyl)acetyl chloride which was used without purification or analysis.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[N:17]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1
Agent: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 4 and 4-chloromethylbenzoic acid as described for compound 83. Crystallized from ethyl acetate. M.p. 189°-190° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:54][C:55](O)=[O:56])=[CH:46]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:55](=[O:56])[CH2:54][C:47]3[C:48]4[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:45]([CH3:44])[CH:46]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c2ccccc21
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-methyl-3-indoleacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 5:95) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(1-methyl-1H-indol-3-yl)-acetamide (0.8 g, 83%) as a yellow solid: mp 231-233° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.53 min. (98%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.54-2.63 (m, 2H), 2.83-2.91 (m, 1H), 3.62 (s, 2H), 3.73 (s, 3H), 4.70 (d, J=5.9 Hz, 2H), 5.10-5.16 (dd, J=5.2 and 12.7 Hz, 1H), 6.99-7.04 (dd, J=7.1 and 7.9 Hz, 1H), 7.12-7.17 (dd, J=7.1 and 7.9 Hz, 1H), 7.21 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.54-7.79 (m, 4H), 8.47 (t, J=5.9 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 32.23, 32.34, 37.86, 48.83, 107.82, 109.50, 118.39, 118.78, 121.07, 121.79, 127.06, 127.47, 128.27, 131.46, 133.19, 134.54, 136.53, 139.38, 166.91, 167.45, 169.77, 171.15, 172.71; Anal. Calcd. for C25H22N4O5: C, 65.49; H, 4.84; N, 12.22. Found: C, 65.11; H, 4.54; N, 12.05.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([N:8]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:21][CH2:20][CH2:19][C:18]([O:17][CH3:16])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC=O
Reactant: CCOC(=O)C(C)NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(C)N(CCCC(=O)OC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of the product of Example 112, step a (794 mg, 3.8 mmol) in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol) followed by Na(OAc)3BH (1.6 g, 7.7 mmol). The mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NaHCO3 solution. The layers were separated and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 column eluting with EtOAc/Hex afforded the desired compound as a colorless liquid (1.11 g, 95%). MS (ESI) mass calcd. C17H25NO4, 307.2. m/z found 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H), 3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m, 2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.Br[C:21]1[C:22]([CH:27]=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:22]=1[CH:27]=[O:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ncccc1-c1cccnc1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
A mixture of 3-tributylstannanyl-pyridine (255 mg, 0.693 mmol), 3-Bromo-pyridine-2-carbaldehyde (123 mg, 0.660 mmol), and Pd(PPh3)4 (53.1 mg, 0.046 mmol) in toluene (4 mL) was heated to 90° C. for 23 h and cooled to room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30, then 0:100) afforded [3,3′]Bipyridinyl-2-carbaldehyde (35 mg, 29%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[IH:19]>>[I:19][C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: I
Reactant: CCCCCCSc1nn2c(=O)cc(Cl)nc2s1
Product: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 8.4 g of the thus obtained 7-chloro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one and 88.2 g of a 57% hydroiodic acid aqueous solution was heated to 95°~110° C. and stirred for 2 hours. After cooling, the solution was filtered. The residue was washed with water and dissolved in toluene. The toluene solution was washed with a sodium hydrogen carbonate aqueous solution, a sodium thiosulfate aqueous solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 9.8 g of 80% pure 7-iodo-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 72%.