Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17]OC)=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[Na+].[Na+].[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[N:34]([C:36](I)=[CH:37][N:38]=2)[CH:35]=1)=[O:29]>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>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[N:34]([C:36]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH3:20])=[CH:37][N:38]=2)[CH:35]=1)=[O:29]
Reactant: COC(=O)c1ccc2ncc(I)n2c1
Reactant: O=C([O-])[O-]
Reactant: COCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOc1c(-c2cnc3ccc(C(=O)OC)cn23)cc(C(C)C)cc1C(C)C
Temperature: 80 °C
Yield: 65.1 %

Procedure:
3,5-Diisopropyl-2-methoxymethoxy-phenyl-boronic acid (455 mg, 1.83 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (191 mg, 0.16 mmol), and 2M sodium carbonate solution (3.31 ml, 3.32 mmol) were added to a solution of 3-iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (500 mg, 1.66 mmol) in toluene (10 mL). This reaction was then heated to 80° C. overnight, then cooled to ambient temperature and partitioned between brine (10 mL) and ethyl acetate (50 mL). The organic layer was dried over MgSO4 and evaporated to a residue. The residue was purified by silica gel chromatography (5% MeOH in dichlorometlane) to yield 3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a yellow solid (411 mg, 65%). 1H NMR (250 MHz, CDCl3): δ 8.71 (s, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.41 (m 1H), 7.19 (d, 1H, J=1.2), 7.08 (d, 1H, J=1.2), 3.85 (s, 3H), 3.38 (m, 1H), 3.29 (q, 2H, J=6.8),2.90 (m, 1H), 1.28 (s, 3H), 1.26 (s, 6H), 1.24 (s, 3H), 0.75 (t, 3H, J=6.8). MS [EI+] 381 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1>O1CCOCC1.CO>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:24][CH:23]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
173 mg (0.15 mmol) of tetrakistriphenylphosphine palladium and 4.4 mL (8.8 mmol) of a 2M sodium carbonate solution is added at ambient temperature to a solution of 1.124 g (4.04 mmol) of ethyl (E)-3-(4-bromophenyl)acrylate in 50 mL of dioxane. 0.689 g (4.404 mmol) of 4-chlorophenylboric acid dissolved in 10 mL of methanol is added to this reaction mixture and refluxed for 5 hours. The reaction mixture is evaporated down, the residue is taken up in dichloromethane, and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate (9:1)). Yield: 0.94 g (74.4% of theory); C17H15ClO2 (M=286.76); calc.: molecular ion peak (M+H)+: 287/289; found: molecular ion peak (M+H)+: 287/289; Rf value: 0.44 (silica gel, petroleum ether/ethyl acetate (40:10)).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[C:23](Cl)[N:22]=[C:21]([Cl:26])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CC(N(C)C)=O>C(O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[C:23]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[N:22]=[C:21]([Cl:26])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(N4CCN(C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2,6-dichloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (10 mg), N-methylpiperazine (10 mg), and DMA (250 μL) were combined in a microwave tube and heated to 100° C. for 30 min. Reaction was cooled to 23° C. and diluted with absolute ethanol and was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the title compound. LCMS-ESI+: calc'd for C32H36Cl2N4O3S: 627.2, 629.2 (M+H+); Found: 627.2, 629.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1(C)C=CC=CC=1>C1CCCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][S:10](=[O:12])(=[O:11])[NH2:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: NS(=O)(=O)Oc1ccccc1Cl
Yield: 58.8 %

Procedure:
This compound was prepared by the procedure used in Example 84. A mixture of 12.8 g (0.1 mole) of 2-chlorophenol, 14.8 g (0.105 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 12.2 g (59%) of the title compound as a white solid, mp 62.5°-63.5° C. (cyclohexane-benzene).
Reaction SMILES: [C:1]([C:4]1[CH:41]=[CH:40][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=2[CH:16]2[C:21]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:20]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[CH2:19][C:18](=[O:39])[NH:17]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C[Si]([C:46]#[CH:47])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[C:1]([C:4]1[CH:41]=[CH:40][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:46]#[CH:47])=[CH:11][C:10]=2[CH:16]2[C:21]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:20]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[CH2:19][C:18](=[O:39])[NH:17]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2ccc(C(N)=O)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-2′-[2-(4-carbamoyl-phenoxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.35 g, 0.5 mmol) was reacted with trimethylsilyl acetylene (0.49 g, 5 mmol), CuI (3 mg), triethylamine (1.52 mL, 15 mmol), and dichlorobis(triphenylphosphine) palladium (0) (28 mg, 0.04 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-2′-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.25 g, 84%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]#[N:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>>[CH3:19][N:20]([CH3:25])[S:21](=[O:23])(=[O:22])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[C:17]#[N:18])=[CH:6][CH:7]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccc(O)cc1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)Oc1ccc(-c2ccc([N+](=O)[O-])cc2C#N)cc1

Procedure:
The procedure of Example 88 was repeated, except that 120 mg of 4′-hydroxy-4-nitro-2-biphenylcarbonitrile was used in place of N-(4′-hydroxybiphenyl-4-yl)methanesulfonamide, and 0.430 ml of N,N-dimethylsulfamoyl chloride was used in place of sulfamoyl chloride. The resulting crude product was purified by TLC (using a 16:1 mixture of chloroform and acetone as the developing solvent) to obtain 97 mg of 2′-cyano-4′-nitrobiphenyl-4-yl N,N-dimethylsulfamate.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:11][C:12]1[C:16]([CH2:17][C:18]2[S:33][C:21]3[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=3[C:19]=2[C:34]([N:36]2[CH2:40][C@H:39]([OH:41])[CH2:38][O:37]2)=[O:35])=[C:15]([CH3:42])[NH:14][N:13]=1>CN(C)C=O.O>[OH:41][C@@H:39]1[CH2:38][O:37][N:36]([C:34]([C:19]2[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]=3[S:33][C:18]=2[CH2:17][C:16]2[C:15]([CH3:42])=[N:14][N:13]([CH:2]([CH3:4])[CH3:3])[C:12]=2[CH3:11])=[O:35])[CH2:40]1
Reactant: Cc1n[nH]c(C)c1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C(C)C)c(C)c1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Iodopropane (0.1 ml) and potassium carbonate (100 mg) were added to a solution of 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (example 11, 100 mg) in dimethylformamide (1 ml) and the mixture stirred at 100° C. After 2 hours, further 2-iodopropane (0.2 ml) and potassium carbonate (200 mg) were added. After a further 16 hours, the mixture was cooled to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). Combined organic extracts were treated with pyrrolidine (0.1 ml) and after 1 hour were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse-phase HPLC with gradient 0.1% aqueous ammonium acetate/acetonitrile elution to give the title compound (58 mg) as a foam. MS (APCI) 504 [M+H]+. δ 1HDMSO 0.87 (6H, d), 1.31 (6H, d), 1.99-2.14 (7H, m), 3.19-3.21 (3H, m), 3.45-4.13 (8H, m), 4.40 (1H, sept), 4.56-4.79 (1H, m), 5.48-5.55 (1H, m).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1.[S:13]1C=CC=C1CC([O-])=O.[K+].[CH3:23][C:24](C)=[O:25]>>[C:24]([S:13][CH2:2][CH2:3][C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)(=[O:25])[CH3:23]
Reactant: O=C([O-])Cc1cccs1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(CCBr)s1
Agent: [K+]
Product: COC(=O)c1ccc(CCSC(C)=O)s1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 6.23 g (25 mmol) of 9c and 5.71 g (50 mmol) of potassium thiolacetate in 100 mL of acetone was heated at reflux for 30 minutes. After cooling to room temperature, the crude reaction mixture was filtered, and the filtrate was concentrated, in vacuo. The residue obtained was partitioned between ether and water (150 mL each). The layers were separated and the aqueous phase was extracted with 100 mL of ether and 100 mL of ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, yielding a red oil which was purified by flash chromatography. Elution with hexane/ethyl acetate (9:1) yielded the product as a yellow solid (5.61 g, 92% yield) mp 67°-68° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:15]1([S:21][C:4]2[CH:3]=[C:2]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Sc2ccccc2)cc1Sc1ccccc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 9.2 %

Procedure:
A mixture of methyl 4-chloro-2-nitrobenzoate (25 g), thiophenol (20.4 g) and potassium carbonate (17.6 g) in N,N-dimethylformamide was stirred at 120° C. for five hours. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate, filtered and evaporated. The product was recrystallised from cyclohexane to give 3.0 g of methyl 2,4-bis(phenylsulphenyl)benzoate as a beige solid, m.p. 123.9° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([CH:23]5[CH2:26][N:25]([CH2:27][CH2:28][O:29]C6CCCCO6)[CH2:24]5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.O1CCOCC1>CO.C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([CH:23]5[CH2:24][N:25]([CH2:27][CH2:28][OH:29])[CH2:26]5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CCOC4CCCCO4)C3)cc1-2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CCO)C3)cc1-2
Reaction time: 3 h
Yield: 32 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (110 mg, 0.22 mmol) in MeOH (3 mL) and DCM (3 mL) was treated with 4N HCl/dioxan (2 mL, 8 mmol) and the mixture left to stand for 3 hours then concentrated in vacuo. The resultant residue was triturated with diethyl ether and dried under vacuum. Further purification by flash chromatography (SiO2, 0-10% 2N NH3/MeOH in DCM) gave 376 (29 mg, 32%). LCMS: RT=6.96 min, [M+H]+=412. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=2.34 Hz), 7.90 (1H, s), 7.15 (1H, dd, J=8.27, 2.35 Hz), 7.01 (1H, d, J=8.26 Hz), 5.94-5.84 (1H, m), 4.40-4.34 (2H, m), 3.89-3.83 (2H, m), 3.84-3.72 (1H, m), 3.59-3.54 (2H, m), 3.41-3.36 (2H, m), 3.28-3.21 (2H, m), 2.71-2.66 (2H, m), 1.62 (6H, d, J=6.65 Hz). 1 Exchangeable proton not seen
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)=[O:26]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)=[O:26]
Reactant: N#CN
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Reactant: COc1cccc(C(=O)CBr)c1
Product: COc1cccc(C(=O)c2sc(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)nc2N)c1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) following the procedure used in Example 24 Mass spectrum (ES) MH+=464.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[NH3:14]>>[C:2]([C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2)#[N:14]
Reactant: ClC(Cl)(Cl)c1nc2ncccc2[nH]1
Reactant: N
Product: N#Cc1nc2ncccc2[nH]1

Procedure:
2-Trichloromethyl-imidazo[4,5-b]pyridine (21.5 g) is added, in small portions, to 34% strength ammonia (250 ml), which is stirred vigorously and kept at about 10° C. After the addition, the reaction mixture is stirred for about one hour, the temperature being allowed to rise to the ambient temperature (20° to 25° C.). The reaction mixture is filtered over silica supercel and the filtrate is acidified to pH=6 with hydrochloric acid (200 ml) of density 1.19, the temperature being kept below 10° C. 2-Cyanoimidazo[4,5-b]pyridine (8 g in total) of melting point of about 200° C. is obtained by filtering off the precipitate, extracting the mother liquors with ethyl acetate and concentrating the extract. Purity: about 80%.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[C:5]1([O:4][C:2](=[O:3])[NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCc1cccc(Oc2ccccc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCc1cccc(Oc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of phenyl chloroformate (0.29 mL, 2.3 mmol) in tetrahydrofuran (10 mL) were added 3-phenoxybenzylamine described in Preparation Example 4 (0.5 g, 2.5 mmol) and triethylamine (0.35 mL, 2.5 mmol) dropwise on an ice bath, and then, the solution was stirred at room temperature for 4 hours. The reaction solution was poured into brine, the solution was extracted with ethyl acetate and concentrated, and the title compound (0.7 g, 2.2 mmol, 88%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH3:17])=[C:4]([Cl:9])[CH:3]=1
Reactant: CCI
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1Cl
Reaction time: 68 h

Procedure:
To a mixture of 4-bromo-2-chlorophenol (10.81 g) and potassium carbonate (8.65 g) in DMF (10 ml) was added at room temperature ethyl iodide (4.17 ml), and the mixture was stirred for 68 hours. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give pale yellow oil of 4-bromo-2-chloro-1-ethoxybenzene (12.28 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[NH2:3].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:2]([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[N:3]=1)([CH3:18])([CH3:17])[CH3:10]
Reactant: NNc1ccncc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccncc2)n1
Yield: 16.9 %

Procedure:
Following the procedure in Example 161A Step 3, 4-hydrazinopyridine hydrochloride (1.0 g, 6.87 mmol) and 4,4-dimethyl-3-oxopentanenitrile (860 mg, 6.87 mmol) were reacted to give 3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-amine (250 mg, 1.16 mmol, 17%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (br s, 2H), 7.69 (br s, 2H), 5.55 (br s, 2H), 5.46 (s, 1H), 1.22 (s, 9H); LC-MS (ESI) m/z 217 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:14]2[CH:15]=[CH:16][C:11]([CH3:17])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 48.9 %

Procedure:
175 g of 4-chlorobenzoyl chloride are added dropwise at about 70° C. to a mixture of 553 g of toluene and 140 g of AlCl3. After completion of the evolution of HCl, the reaction mixture is added to 1 1 of water, and the solid obtained is separated off and recrystallized from 20 ethanol/toluene (50:1 parts by wt). 112.7 g of 4'-chloro-4-methylbenzophenone (melting point 129° C. to 130° C.; content of 4,4,-isomer>99.5% by GCSA) are obtained. 4-(4-Chlorobenzoyl)benzoic acid (melting point 256° C. to 258° C.) is accessible from this in 95% yield by oxidation. This acid is converted into the acid chloride by phosgenation. 97.7 g of 4-(4-chlorobenzoyl)benzoyl chloride, dissolved in 250.0 g of fluorobenzene, are added dropwise at 60° C. to 85° C. to a mixture of 254.5 g of fluorobenzene and 49.0 g of AlCl3. After the evolution of gas is complete, the reaction mixture is added to 0.5 1 of water and, after distillative removal of excess fluorobenzene, the precipitate is separated off, washed until neutral and recrystallized from chlorobenzene. Yield of 1-(4chlorobenzoyl-4-(4-fluorobenzoyl)benzene: 54.0 g (melting point 211° C. to 212° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2Cc2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-benzylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.79 minutes; C28H26C12N4O2 (521.45); mass spectrum: (M−H)−=520/522/524 (chlorine isotope).
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:33])=[C:12]([C:18]([I:32])=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][O:28]C(C)(C)[O:26]3)=[O:24])[C:20]=2[I:21])[CH2:13]CC([O-])=O)=[O:8])[CH2:4][O:3]1.[OH2:35]>CO.Cl>[OH:26][CH:25]([CH2:29][OH:28])[C:23]([NH:22][C:19]1[C:18]([I:32])=[C:12]([C:11]([I:33])=[C:10]([NH:9][C:7](=[O:8])[CH:5]([OH:6])[CH2:4][OH:3])[C:20]=1[I:21])[CH2:13][OH:35])=[O:24]
Reactant: O
Reactant: CC1(C)OCC(C(=O)Nc2c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C3COC(C)(C)O3)c2I)O1
Agent: Cl
Solvent: CO
Product: O=C(Nc1c(I)c(CO)c(I)c(NC(=O)C(O)CO)c1I)C(O)CO
Reaction time: 4 h

Procedure:
N,N′-Bis(2,2-dimethyl-1,3-dioxolane-4-carbonyl)-3,5-diamino-2,4,6-triiodobenzylacetate (1.25 g, 1.55 mol) was dissolved in a mixture of water (50 ml), methanol (25 ml) and concentrated HCl (0.5 ml). After stirring for 4 h, the solution was neutralized with aqueous NaH2PO4 and the solvents were removed by evaporation. The residue was dissolved in water (10 ml) and the pH was adjusted to 12 with aqueous NaOH. After 30 min, the solution was again neutralized and the solvent was evaporated. The product was purified by preparative HPLC. Yield: 483 mg (45%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].O>CN(C=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][NH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:13]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CBr
Reactant: Nc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 7-(4-Amino-3-benzyloxybenzyl)-azepan-2-one (600 mg, 1.7 mmol) and potassium carbonate (345 mg, 2.5 mmol) in DMF (10 mL) is added methyl bromoacetate (383 mg, 2.5 mmol). The mixture is stirred at 60° C. for 4 h then is allowed to cool to RT. It is poured into water and extracted with EtOAc and the organic phase is washed with water (3×), brine (1×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.