Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](N1CCCC1)=[CH:6]2.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[N+:24]=[N-:25])=[CH:20][CH:19]=1>>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[C:4]1[N:25]=[N:24][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:27][CH:26]=3)[C:5]=1[CH2:6]2
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: CN1C2C=C(N3CCCC3)CC1CCC2
Product: COc1ccc(Cn2nnc3c2CC2CCCC3N2C)cc1
Temperature: 50 °C
Yield: 57.6 %

Procedure:
A mixture of 9-methyl-3-(pyrrolidin-1-yl)-9-azabicyclo[3.3.1]non-3-ene (1.2 g, 5.9 mmol) and 4-methoxybenzylazide (0.96 g, 5.9 mmol) was heated at 50° C. for 2 days. The crude mixture was purified by prep HPLC to afford the product (1.0 g, 3.4 mmol, 57% yield) as yellow oil.
Reaction SMILES: [K].CC(C)([O-])C.[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10]P(=O)(OCC)OCC.[C:23]1([CH3:45])[CH:28]=[CH:27][C:26]([N:29]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.Cl>O1CCCC1.O>[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]=[CH:44][C:41]1[CH:40]=[CH:39][C:38]([N:29]([C:30]2[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=2)[C:26]2[CH:27]=[CH:28][C:23]([CH3:45])=[CH:24][CH:25]=2)=[CH:43][CH:42]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Reactant: CCOP(=O)(Cc1ccccc1O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
14.8 g of kalium-tert-butoxide and 50 ml of tetrahydrofuran were put in a reaction reservoir having a mixer, a thermometer and a dropping funnel. Under a nitrogen stream, a solution wherein 9.90 g of the diethyl 2-hydroxybenzylphosphonate and 5.44 g of 4-(di-para-tolylamino)benzaldehyde were dissolved in tetrahydrofuran was slowly dropped therein at a room temperature, and the reaction therein is further performed for 2 hrs at the same temperature. Then, water was added therein while cooling the reaction product with water, a hydrochloric acid solution having a normal concentration of 2 was added therein to acidize the reaction product, and the tetrahydrofuran was removed by an evaporator to extract a crude product with toluene. The toluene phase was washed with water, a sodium hydrogen carbonate solution and a saturated saline in this order, and magnesium sulfate was further added thereto to dehydrate the toluene phase. After filtered, the toluene was removed therefrom to prepare an oily crude product, and the oily crude product was further column-refined with silica gel to crystallize 5.09 g of 2-hydroxy-4′-(di-para-tolylamino)stilbene in hexane at a yield of 72%, having a boiling point of 136.0 to 138.0° C.
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[Br:10][C:11]1[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:24][C:25]1[C:30]2[NH:31][C:32](=[O:34])[O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1.BrBr.ClCl>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([C:27]2[CH:26]=[C:25]([CH3:24])[C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:19])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: BrBr
Agent: ClCl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)c2ccnc(Br)c2)cc2oc(=O)[nH]c12
Temperature: 130 °C
Reaction time: 5 h

Procedure:
2.20 mL (30.0 mmol) thionyl chloride and 0.390 mL (4.80 mmol) DMF were added to 2.00 g (9.90 mmol) 2-bromopyridine-4-carboxylic acid in 30 mL DCM and refluxed for 2 h. The reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was combined with 6.24 g (46.8 mmol) aluminium trichloride and 1.50 g (10.1 mmol) 4-methyl-3H-benzoxazol-2-one and the mixture obtained was stirred overnight at 110° C. and for 5 hours at 130° C. The mixture was decomposed with ice water and extracted twice with DCM. The organic phases were dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE/MeOH and suction filtered. The product obtained is a mixture of the corresponding bromine and chlorine compound (40/60).
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].Cl>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC(COCCO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(COCCOS(C)(=O)=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 19.0 g of 1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane and 95.0 ml of methylene chloride containing 9.1 ml of methanesulfonyl chloride was dropwise added 16.4 ml of triethylamine with ice cooling over 1 hour. The resulting mixture was stirred for 10 minutes at the same temperature and further for 1 hour at room temperature. The reaction mixture was added to a mixture of 50.0 ml of methylene chloride and 50.0 ml of ice water. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 24.5 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-methanesulfonyloxyethoxy)ethane.
Reaction SMILES: [CH3:1][NH:2][NH:3][C:4]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[NH:5].[CH:12](O)=O>>[Br:11][C:8]1[S:7][C:6]([C:4]2[N:5]=[CH:1][N:2]([CH3:12])[N:3]=2)=[CH:10][CH:9]=1
Reactant: O=CO
Reactant: CNNC(=N)c1ccc(Br)s1
Product: Cn1cnc(-c2ccc(Br)s2)n1

Procedure:
A mixture of compound 5-bromo-thiophene 2-carboximidic-N′-methyl-hydrazide (4BW) (13 g) in formic acid (100 ml) was refluxed overnight and concentrated. The residue was treated with sat. NaHCO3, and extracted with EtOAc three times. The combined organics were dried over MgSO4. After concentration, compound 5BW was purified by column using 80% EtoAc/hexane to yield light yellow colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:22]1[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=1)[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Temperature: 70 °C
Yield: 45.3 %

Procedure:
To a solution 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (4.7 g, 24.5 mmol) in DMF (250 mL) was added Cs2CO3 (8.0 g, 24.5 mmol) followed by 2-chloro-benzothiazole (3.0 mL, 4.2 g, 24.5 mmol) and the reaction mixture was heated (70° C., 12 h). The reaction mixture was cooled (rt) and concentrated in vacuo. The resulting residue was partitioned between EtOAc (200 mL) and brine (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×300 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-40%) to provide the title compound as a colorless foam (3.6 g, 45%). MS (ESI): mass calcd. for O17H12N2O3S, 324.1; m/z found, 325.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.17 (s, 1H), 7.77-7.63 (m, 3H), 7.46-7.42 (m, 1H), 7.42-7.34 (m, 1H), 7.30-7.26 (m, 1H), 7.23-7.19 (m, 1H), 7.14 (dd, J=8.7, 2.1, 1H), 3.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[C:33]([O:35]CC)=[O:34])=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.CO.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3OC)cccc2c1CCCOc1ccc(Cl)c2ccccc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1cccc2c(CCCOc3ccc(Cl)c4ccccc34)c(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 65A (70 mg) in THF (2 mL), methanol (1 mL) and water (1 mL) was treated with LiOH.H2O (100 mg) and stirred at ambient temperature overnight. The mixture was acidified with 5% aqueous HCl and extracted with ethyl acetate. The extract was washed with water, brine and dried (Na2SO4), filtered and concentrated. The concentrate was dissolved in 1:1 DMSO/methanol and purified by reverse phase HPLC (C18, 20 to 100% acetonitrile/water/0.1% TFA). 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.38 (dd, 1H), 8.15 (dd, 1H), 7.72 (d, 1H), 7.35-7.57 (m, 5H), 7.08-7.21 (m, 3H), 6.65 (d, 1H), 4.18 (t, 2H), 3.82 (s, 3H), 3.47 (t, 2H), 2.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH:14]2[O:16][CH2:15]2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: ClCC1CO1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1c(Cl)cc(OCC2CO2)cc1Cl
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dichloro-4-hydroxy benzaldehyde (3.0 gm 0.0167 m) in 1.5 N sodium hydroxide (25 m) at 50° is added epichlorohydrin (4.4 gm, 0.048 m). After stirring at 50° for 3 hours, the solution is cooled and extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro-4-(2,3-epoxypropoxy)-benzaldehyde (3 g) which is used without further purification.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH:11]=2)[C:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:5]1[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37]C)=[O:36])[CH:2]=[CH2:3]>CCOC(C)=O.[Pd]>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH:11]=2)[C:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:5]1[CH2:33][C:34]([CH3:39])([CH3:40])[C:35]([OH:37])=[O:36])[CH2:2][CH3:3]
Reactant: C=CCn1c(CC(C)(C)C(=O)OC)c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCn1c(CC(C)(C)C(=O)O)c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
A solution of methyl 3-[N-allyl-3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (Example 42, methyl ester) (190 mg) was hydrogenated in EtOAc (4 mL) in the presence of 5% Pd on charcoal at atmospheric pressure for 1 hour. Filtration on Celite pad and evaporation of liquors afforded the methyl ester of the title product. Hydrolysis of this ester under the conditions described in Step B of Example 1 provided the title compound.
Reaction SMILES: O[CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH:5]23.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].C(=O)([O-])O.[Na+]>C(#N)C>[C:26]([CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:3]1[CH2:4][CH:5]23)(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)C1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
In 2,500 ml of acetonitrile were dissolved 500 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furan-7-carboxylate and 318 g of triethylamine. To the solution below 15° C., 288 g of methacrylic chloride was added dropwise. The solution was stirred at room temperature for 2 hours, another 32 g of methacrylic chloride added, and the solution stirred overnight. A saturated aqueous solution of sodium hydrogen carbonate, 500 ml, was added to the reaction solution, followed by ordinary work-up. Recrystallization from hexane yielded 437 g of the title compound (yield 69%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.C([Mg]Br)(C)C.O1CCCC1.[CH3:24][CH2:25][C:26](=[O:31])[CH2:27][CH2:28]CC.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([C:5]1[S:6][C:2]([C:26]([CH2:27][CH3:28])([OH:31])[CH2:25][CH3:24])=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCCCC(=O)CC
Reactant: CCOC(=O)c1cc(Br)sc1CC
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(O)(CC)CC)sc1CC
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (3.00 g) synthesized in Example 69 (4) in tetrahydrofuran (50 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (13.7 mL) at −45° C. After stirring under an argon atmosphere for 1 hr, 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (13.7 mL) was added dropwise, and the mixture was stirred for 1 hr. 3-Heptanone (6.04 mL) was added dropwise, and the mixture was stirred at −45° C. for 1 hr, and at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title compound (3.06 g, quantitative) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][NH:8][C:6]1[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=[C:2]([NH:27][C:26]2[CH:25]=[CH:24][C:23]([N:21]3[CH:22]=[C:18]([CH3:17])[N:19]=[CH:20]3)=[CH:29][CH:28]=2)[N:7]=1
Reactant: Cc1cn(-c2ccc(N)cc2)cn1
Reactant: CNc1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNc1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)cc2)n1
Temperature: 120 °C
Yield: 40.2 %

Procedure:
A mixture of 2-chloro-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (85 mg, 0.33 mmol), 4-(4-methyl-1H-imidazol-1-yl)aniline (100 mg, 0.58 mmol), cesium carbonate (217 mg, 0.67 mmol), palladium(II) acetate (11 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)-biphenyl (17 mg, 0.05 mmol) in dioxane (3 mL) was heated in a microwave reactor under notrogen atmosphere at 120° C. for 90 min. The reaction mixture was filtered through a pad of diatomeous earth which was eluted with MeOH. The mixture was partitioned between EtOAc and sodium hydroxide (aq, 1 M). The organic phase was separated, dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a solid 52 mg, (40%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH2:25]Br)[N:24]=[C:14]12)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH2:6]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH2:25][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:24]=[C:14]12)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1c(CBr)nc2n(Cc3ccccc3)c3ccccc3n12
Reactant: CCNCC
Solvent: c1ccccc1
Product: CCOC(=O)c1c(CN(CC)CC)nc2n(Cc3ccccc3)c3ccccc3n12
Yield: 96 %

Procedure:
Add 1.04 ml (10 mmol) of diethylamine to a hot solution of 9-benzyl-2-bromomethyl-3-ethoxycarbonylimidazo[1,2-a]benzimidazole (2.01 g, 5 mmol), prepared as described for the alkylated analogues in Khim. Farm. ZH 88, 22 (7), 815-9, in 20 ml of benzene. Heat at reflux for one hour, cool. Remove the resulting precipitate, evaporate the benzene, and the residue is recrystallised by hexane to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:4](=[O:15])[O:3]1.C=O.[OH-].C[N+](C)(C)C.[C:25](O)(=[O:27])C>N1C=CC=CC=1.CO>[CH3:1][C:2]1([CH3:16])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])([CH2:25][OH:27])[C:4](=[O:15])[O:3]1
Reactant: CC(=O)O
Reactant: CC1(C)OC(=O)C(c2ccc(Cl)cc2Cl)O1
Agent: C=O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: CC1(C)OC(=O)C(CO)(c2ccc(Cl)cc2Cl)O1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
104.4 g (0.4 mole) of 2,2-dimethyl-4-(2,4-dichlorophenyl)-1,3-dioxolan-5-one are dissolved in 700 ml of pyridine and to the solution are added 48 g of paraformaldehyde. Then 40 ml of a 40% solution of tetramethylammonium hydroxide in methanol are slowly added dropwise. The mixture is stirred for 12 hours, cooled to -5° C., and a solution of 100 ml of glacial acetic acid and 400 ml of pyridine is added dropwise until the pH value is 6.5 to 7. The reaction solution is poured into ice-water and extracted with methylene chloride. The extract is dried over sodium sulfate and the product is crystallised by addition of diethyl ether. The crystalline precipitate is washed with a small amount of diethyl ether and petroleum ether. It has a melting point of 182°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.P(Br)(Br)[Br:14].CCCCC>C(Cl)Cl>[Br:14][CH2:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH3:12])[CH:6]=1
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)n1
Solvent: CCCCC
Solvent: ClCCl
Product: COc1cc(CBr)cc(OC)n1
Reaction time: 10 h

Procedure:
1 g of (2,6-dimethoxypyridin-4-yl)methanol, prepared according to J. Heterocl. Chem., 1974, 11, 251, is dissolved in 20 ml of CH2Cl2, 0.84 ml of PBr3 is added and then the mixture is left stirring at for 10 hours. Pentane is added and the precipitate formed is filtered off, washed with pentane and then dried to produce 850 mg of the expected compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:35])[CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)OC(C)(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid tert-butyl ester gave the title compound.
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[CH:5]([OH:7])=O.C(OC(=O)C)(=O)C.[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[CH2:33][CH2:34][N:26]([C:27]=34)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[NH:23]2)[CH2:18][CH2:17]1>CO>[CH:1]([OH:4])=[O:3].[CH:5]([N:23]1[CH:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[CH2:33][CH2:34][N:26]([C:27]=23)[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]1=2)=[O:7]
Reactant: CC(=O)O
Reactant: CN1CCC(C2Nc3ccccc3N3CCc4cccc2c43)CC1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN1CCC(C2c3cccc4c3N(CC4)c3ccccc3N2C=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of acetic acid (14.1 ml) and formic acid (14.8 ml) was prepared at -10° C. (methanol-ice) over a period of 1.5 hours. This solution, the mixed formic/acetic anhydride reagent, was added to 6-(1-methylpiperidin-4-yl)-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (16 gm) at room temperature in one portion. The mixture was stirred for 30 minutes. The resulting solution was treated with methanol (30 ml) and concentrated to an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]1[NH:26][C:34](=[O:35])[NH:28][N:27]=1)=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3cccc(Cl)c23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Yield: 35.9 %

Procedure:
To a mixture of (S)-tert-butyl 3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (450 mg, 1.1 mmol) in dioxane (10 mL) was added CDI (360 mg, 2.2 mmol). The resulting mixture was heated to reflux for 2 hours and was subsequently concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (170 mg, 45%). ESI-MS m/z [M+H]+ 431.1.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1)C)(C)(C)C>C1(C)C=CC=CC=1.CC(C)=O>[CH3:6][NH:7][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3C#N)cn(Cc3ccccn3)c2c1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CNc1ccc2c(Sc3ccccc3C#N)cn(Cc3ccccn3)c2c1

Procedure:
v)—Following a procedure analogous to that described under step i of Example 2, the product obtained in the previous step (0.150 g, 0.33 mmol) was methylated to give, after column chromatography (toluene/acetone 8:2), [3-(2-cyano-phenylsulfanyl)-1-pyridin-2-ylmethyl-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (0.044 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([F:15])[CH:3]=1.O(C1C=CC([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=CC=1C#N)C1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[F:15][C:4]1[CH:3]=[C:2]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)[CH:7]=[CH:6][C:5]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cc(Br)ccc1Oc1ccccc1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CC1(C)OB(c2ccc(Oc3ccccc3)c(F)c2)OC1(C)C

Procedure:
The title compound was prepared in a 65% from 4-bromo-2-fluoro-1-phenoxybenzene in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 7.49(dd, 2H), 7.41(m, 2H), 7.18 (t, 1H), 7.08(d, 1H), 7.05(d, 2H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, I mmin) tr 14.63 min.