Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OCCN1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1CCOC1=O

Procedure:
The 3-(2-hydroxyethyl)-2-oxazolidinone (Frinton Laboratories, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound which was used directly in the next reaction.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]1[CH2:15][O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])=O)(C)(C)C.[ClH:31].CCOCC>CO>[ClH:31].[ClH:31].[ClH:31].[C:25]1([N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][CH2:15][C@@H:9]3[CH2:10][N:11]([CH3:14])[CH2:12][CH2:13][NH:8]3)=[O:18])[CH2:20][CH2:21]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)[C@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN1CCN[C@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of (S)-4-methyl-2-(4-phenyl-piperazine-1-carbonyloxymethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.65 g, 3.9 mmol) in MeOH (10 mL) was added 2M HCl in Et2O solution (11.8 mL, 23.6 mmol). The reaction was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 15% (over 75 min) MeOH in water with 0.1% TFA. The material was then purified further by reverse phase HPLC(YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 50% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water). The pure product was stirred in 4M aq HCl solution (10 mL) for 4 hours before being concentrated in vacuo. The resulting oil was washed with heptane, concentrated in vacuo and then dried in a vacuum oven overnight to afford the [(2S)-4-methylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate trihydrochloride salt (1.63 g, 96%) as a pale brown solid.
Reaction SMILES: [Mg].[CH3:2][C:3]1([CH3:10])[C:7]([CH3:9])([CH3:8])[O:6][BH:5][O:4]1.Br[CH2:12][C:13]([CH3:15])=[CH2:14].Cl>C1COCC1>[CH3:2][C:3]1([CH3:10])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([CH2:14][C:13]([CH3:15])=[CH2:12])[O:4]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C=C(C)CBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(C)CB1OC(C)(C)C(C)(C)O1

Procedure:
To a suspension of magnesium turning (1.139 g, 46.9 mmol) in THF (65.1 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.67 mL, 39.1 mmol) at room temperature under nitrogen. 3-bromo-2-methylprop-1-ene (3.97 mL, 39.1 mmol) was added slowly, after 30 min, more 3-bromo-2-methylprop-1-ene (3.97 mL, 39.1 mmol) was added, The reaction mixture was stirred at room temperature for 1 h. heptanes was added, followed by 1N HCl. The reaction mixture was then extracted by heptanes. The organic was washed by water and brine, dried and concentrated to yield 4,4,5,5-tetramethyl-2-(2-methylallyl)-1,3,2-dioxaborolane. The product was used in the next step without purification, 1H NMR (400 MHz, CDCl3) δ ppm 4.67 (d, J=6.7 Hz, 2H), 1.77 (s, 3H), 1.34-1.20 (m, 12H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:5][NH:4][C:3]([NH:2][CH3:1])=[S:6])=[O:11]
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClC(Cl)Cl
Product: CNC(=S)NNC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred room temperature suspension of 4-methylthiosemicarbazide (7.9 g, 7.5×10-2 mole) and CHCl3 (190 ml), 2-fluorobenzoyl chloride (9.4 ml, 7.9×10-2 mole) was added dropwise. After stirring overnight at room temperature, the precipitate was collected by filtration and the product was washed with two portions of Et2O. Drying by suction gave a colorless powder which was used without further purification in the subsequent cyclization step.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.Cl.N[OH:18].[OH-].[Na+].O>C(O)(=O)C>[OH:18][NH:2][CH:4]=[N:5][C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: CN(C)C=NC(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C=Cc1ccccc1)N=CNO
Temperature: 5 °C
Yield: 89.4 %

Procedure:
N-[(Dimethylamino)methylene]-cinnamamide (1.0 g, 5.0 mmol) was added to a solution of hydroxylamine hydrochloride (415 mg, 6.0 mmol) in acetic acid (5 mL of 70% aqueous) and aqueous NaOH (1.2 mL, 5 M, 6.0 mmol). After stirring for 1.5 h water (5 mL) was added, and the reaction mixture was cooled to 5° C. in an ice bath. The solution was partitioned between ethyl acetate and water, and the organics were dried over Na2SO4, then concentrated in vacuo to afford N-[(hydroxyamino)methylene]-cinnamamide (850 mg, 90%). This material was carried on to the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:13]2[C:9]([S:10][C:11]([CH3:15])=[C:12]2[CH3:14])=[N:8][CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:15][C:11]1[S:10][C:9]2=[N:8][CH:7]=[C:6]([CH2:4][OH:3])[N:13]2[C:12]=1[CH3:14]
Reactant: CCOC(=O)c1cnc2sc(C)c(C)n12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc2ncc(CO)n2c1C

Procedure:
A solution of 2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester (Formula A-4) (1.68 g) in THF (50 mL) at 0° was treated with LiAlH4 (0.38 g) and reacted at 25° for 1.5 hours. Excess reagent was quenched by sequential addition of water and 15% sodium hydroxide. The resulting mixture was diluted with THF (100 mL), filtered, and the filtrate was evaporated to a residue of crude 2,3-Dimethylimidazo[2,1-b]thiazole-5-methanol (Formula A-5) (1.04 g). Crystallization from isopropanol solution gave pure 2,3-Dimethylimidazo[2,1-b]thiazole-5-methanol (Formula A-5), m.p. 166-167°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[C:24]=1[C:25]([OH:27])=[O:26].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[C:24]=1[C:25]([OH:27])=[O:26]
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(Br)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 49.2 %

Procedure:
A suspension of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2 g, 5.84 mmols), 2-amino-6-bromobenzoic acid (2.53 g, 11.69 mmols), and N-ethyl-N-(1-methylethyl)-2-propanamine (7.55 g, 58.4 mmols) in 2-propanol (150 ml) was heated at 90° C. for 5 days. The solvent was removed, residue redissolved in DCM (150 ml), washed with 1M HCl(100 ml), organic layer separated, adsorbed onto silica gel, and purified by silica gel chromatography (DCM to 10% MeOH/DCM). The crude product was then recrystallized from ethyl acetate/hexanes to obtain 2-bromo-6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid (1.5 g, 49%). ESIMS (M+H)+=521.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:20]Br>C(Cl)Cl.[Fe]>[Br:20][C:8]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:19][C:11]2[C:12]([CH3:18])([CH3:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: BrBr
Reactant: CCCCCCc1ccc2c(c1)C(C)(C)CCCC2
Agent: [Fe]
Solvent: ClCCl
Product: CCCCCCc1cc2c(cc1Br)CCCCC2(C)C
Reaction time: 0.5 h

Procedure:
This 3.08 g of 2-hexyl-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene were dissolved in 35 ml of CH2Cl2, treated at 0° with a spatula tip of Fe powder and then reacted with a solution of 0.67 ml of Br2 (1.1 eq.) in 5 ml of CH2Cl2. After 30 min., the mixture was poured on to ice, extracted with diethyl ether, washed with bisulphite solution and NaCl soln., dried over Na2SO4 and evaporated to dryness. Flash chromatography on SiO2 (hexane) gave 3.21 g of 2-bromo-3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene as a colorless oil (GC purity: 82%, moreover 2% ed., 2.6% regioisomer, 8.3% dibromo compound and further prod.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1([NH2:9])[CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24])[CH3:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23]([NH:9][C:5]1([CH2:4][C:3]([O:2][CH3:1])=[O:10])[CH2:8][O:7][CH2:6]1)=[O:24])[CH3:19]
Reactant: COC(=O)CC1(N)COC1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NC1(CC(=O)OC)COC1
Temperature: 25 °C

Procedure:
(3-Amino-oxetan-3-yl)-acetic acid methyl ester (95 mg; 0.655 mmol) dissolved in CH2Cl2 (5 ml) and triethylamine (0.22 ml; 1.6 mmol) are cooled to −5° C. Chlorocarbonyl-acetic acid ethyl ester (0.1 ml; 0.79 mmol) is slowly added under stirring. The reaction mixture is warmed to room temperature, stirred for 20 minutes, poured on a saturated solution of NaHCO3 and extracted with CH2Cl2 three times. The organic phases are combined, dried over Na2SO4, filtered and evaporated to dryness. Chromatography (SiO2; Hexanes/acetone 4:1) yields the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 8.93 (s, 1H); 4.54 (dd, 4H); 4.09 (q, 2H); 3.60 (s, 3H); 3.23 (s, 2H); 3.10 (s, 2H); 1.19 (t, 3H). MS (m/z) ES+: 260 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[CH:23][CH:22]=2)=[CH:17][N:16]=1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>O1CCOCC1>[F:30][CH:28]([F:29])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[N:20][C:15]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=3)=[N:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1

Procedure:
A mixture of ethyl 2-(4-aminophenyl)acetate (8 mmol), 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (4 mmol), and p-TSA (2 mmol) in 1,4-dioxane (4 mL) are heated at reflux for 4 h. The mixture is poured onto 1 N HCl. The solid is filtered, washed with 1 N HCl and dried to afford ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)acetate 31 as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 2H), 7.92 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.18 (d, J=9.1 Hz, 2H), 6.49 (t, J=73.5 Hz, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 1.19 (t, J=7.1 Hz, 3H). MS (m/z) (M+1)+: 400.1.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1ccccn1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccccn2)c(=O)[nH]c1=O
Yield: 39.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (145 mg, yield: 39.9%).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:24]3[S:25][CH:26]=[CH:27][C:23]=3[CH3:22])[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3sccc3C)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 3-methylthiophene-2-boronic acid pinacol ester (129 mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(3-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.24 (s, 1H), 7.1-7.2 (m, 2H), 7.0 (dd, 1H), 6.6 (s, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.64 (m, 1H), 3.2 (m, 1H), 2.8-3.17 (m, 7H), 2.6 (t, 2H), 2.4 (s, 3H), 2.2 (t, 2H), 1.8 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21]O)=[C:16]([CH3:23])[C:15]=3[CH:24]=2)=[O:9])=[N:6][CH:7]=1.CS([Cl:29])(=O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21][Cl:29])=[C:16]([CH3:23])[C:15]=3[CH:24]=2)=[O:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(CCl)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.3 %

Procedure:
To a solution of 5-chloro-N-(8-(hydroxymethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide from step 3B (52 mg, 0.15 mmol) in dichloromethane (1 mL) was added methanesulfonylchloride (0.015 mL, 0.20 mmol) and DIPEA (0.048 mL, 0.27 mmol). The mixture was stirred at rt for 20 h. The mixture was subjected to chromatography (hexanes-100% EtOAc) to give 5-chloro-N-(8-(chloromethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide (30 mg, 0.083 mmol, 55% yield). LCMS (M+H)+=361.2. 1H NMR (500 MHz, chloroform-d) δ 9.81 (br. s., 1H), 8.58 (dd, J=2.3, 0.6 Hz, 1H), 8.27 (dd, J=8.4, 0.6 Hz, 1H), 7.90 (dd, J=8.4, 2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.1, 2.3 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 4.37 (s, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.21 (s, 3H), 2.17 (quin, J=7.1 Hz, 2H), 2.05-1.98 (m, 2H)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[I-:12].[K+].C(OCC)(=O)C>C(O)(=O)C>[Cl:8][C:7]1[C:2]([I:12])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc(I)c(Cl)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 2,3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100° C. for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 mL) added. The organic phase was separated and washed with water (2×100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33](OC)[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[C:37](CC)=[O:38].C1(C)C(C)=CC=CC=1>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([O:38][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(OC)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCC(C)=O
Solvent: Cc1ccccc1C
Product: CCCCc1nc2cc(OC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-4-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene=1:2)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccc(F)cc3)CC2)C1

Procedure:
Compound 760 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 4-fluoro-benzoyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0098 g, 2% yield). HRMS (M−H) calcd for C26H26N4Cl2O4F: 547.13151. found: 547.1310.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[N:7]=1
Reactant: CSc1nc(N)nc(-c2occc2C)c1C#N
Reactant: NCc1ccccc1
Solvent: COCCOC
Product: Cc1ccoc1-c1nc(N)nc(NCc2ccccc2)c1C#N

Procedure:
From 2-amino-4-(3-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile and benzylamine in DME. EI-MS m/e (%): 305 (M+, 40), 304 ([M—H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([Cl:33])[CH:25]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:33][C:26]1[CH:25]=[C:24]([CH:32]=[CH:31][C:27]=1[C:28](=[O:29])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)[CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)-2-chlorobenzoic acid via Procedure G to yield tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 54 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 477.3 (M)+.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:3]2=[N:1][N:2]=1
Reactant: NNc1ncccc1-c1cccnc1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2c(-c3cccnc3)cccn12
Temperature: 130 °C

Procedure:
A 1.0 g portion of 2-hydrazino-3,3'-bipyridine was dissolved in 5 ml of triethyl orthoacetate and heated at 130° C. for 1.5 hours. The volatiles were removed at reduced pressure and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol (9:2). The resulting solid was recrystallized from methylene chloride-hexane, giving the desired product as a tan powder, mp 112.5°-115° C.
Reaction SMILES: CO.[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]CCCC)=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1.[OH-].[K+]>O>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: CCCCOC(=O)CCOCCc1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To methanol (5 mL) solution of 5.00 g of butyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added water (5 mL) solution of 1.10 g of potassium hydroxide, which was then stirred at room temperature for 2 hours. This reaction mixture was distilled off under reduced pressure, to which were added 30 mL of toluene and 30 mL of water. The pH was adjusted to 1.6 with 3.5 mL of 6 mol/L hydrochloric acid. The organic layer was separated, followed by distilling off the solvent under reduced pressure. Thereto were added 15 mL of toluene and 30 mL of cyclohexane. The precipitate was collected by filtration to provide 3.60 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid as white solid form.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[O:20][C:19]([CH:21]2[O:26][CH2:25][CH2:24]C[O:22]2)=[CH:18][CH:17]=1)CCC>CN(C=O)C.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>[O:26]1[CH2:25][CH2:24][O:22][CH:21]1[C:19]1[O:20][C:16]([N:3]2[CH:2]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:17][CH:18]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCCO2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccc(C4OCCO4)o3)cc2c1
Reaction time: 0.25 h

Procedure:
10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1979, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PPh3)4 is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-1, 3-dioxane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(1,3-dioxolan-2-yl)furyl)indazole are obtained.