Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)(=O)C.[CH:8]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:24]=1)[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:16])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.ClCCl>[CH3:1][N:2]([CH2:8][C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:24]=1)[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:16])[CH3:3]
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Dimethylamine (60 uL, 0.33 mmol) and acetic acid (19 uL, 0.33 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 100 mg, 0.33 mmol) in DCE (5 ml). The solution was stirred for 3 hours at 50° C. then sodium triacetoxyborohydride (105 mg, 0.50 mmol) was added. The mixture was stirred overnight. Saturated NaHCO3 solution (5 ml) was then added and the mixture was stirred for 5 minutes. The organic layer was diluted with dichloromethane (5 ml), separated and dried (MgSO4). The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as an opaque solid. 17 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:40][C:41]1[NH:45][N:44]=[N:43][N:42]=1>CN(C)C=O.C(Cl)Cl>[NH:42]1[C:41]([NH:40][C:20](=[O:21])[CH2:19][O:18][C:17]2[CH:23]=[CH:24][C:14]([CH2:13][CH2:12][NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[N:45][N:44]=[N:43]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)Nc1nnn[nH]1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 7.30 g. (20 mMol) 4-[2-(4-chlorobenzenesulphonamido)-ethyl]-phenoxyacetic acid (preparation see European Patent Specification No. 0,239,907) and 2.20 ml. 4-methylmorpholine in 60 ml. dry methylene chloride is added dropwise at -10° C. 2.76 g. (20 mMol) isobutyl chloroformate, dissolved in 40 ml. dry methylene chloride, within the course of 15 minutes. After a further 15 minutes, a solution of 3.06 g. (20 mMol) 5-amino-1,2,3,4-tetrazole and 20 ml. dimethylformamide are added dropwise thereto within the course of 15 minutes. After stirring for 1 hour at -10° C., the reaction mixture is allowed to come to ambient temperature overnight, the solvent is distilled off, the oily residue is taken up in ethyl acetate and shaken out with 2N aqueous sodium hydroxide solution. The aqueous alkaline phases are acidified with 2N sulphuric acid and the resultant precipitate is filtered off with suction and thoroughly washed with water. After crystallisation from ethanol, there are obtained 4.20 g. (48% of theory) of colourless crystals; m.p. 227.5°-229.5° C.
Reaction SMILES: [C:1]([CH:9]([CH:14]([CH3:16])[CH3:15])[CH2:10][C:11](O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([NH:19][NH2:20])=O.C(C(C)C(C)C(O)=O)(=O)C1C=CC=CC=1.C([NH:39][NH2:40])(=O)C>>[CH:14]([C:9]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:20][N:19]2[CH:17]=[N:39][N:40]=[C:11]2[CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)C(CC(=O)O)C(=O)c1ccccc1
Reactant: NNC=O
Reactant: CC(=O)NN
Agent: CC(C(=O)O)C(C)C(=O)c1ccccc1
Product: CC(C)c1cc2nncn2nc1-c1ccccc1

Procedure:
The procedure of Example 4 is repeated substituting equimolecular amounts of 3-benzoyl-3-isopropyl-propionic acid and N-formylhydrazine for the 3-benzoyl-2,3-dimethyl-propionic acid and N-acetylhydrazine employed in that example. There is thus obtained the title compound in equally good yield.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:2]1.[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([CH3:34])([CH3:33])[CH2:27][C:28](=[O:32])[NH:29]2)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:33][C:26]1([CH3:34])[C:25]2[C:30](=[CH:31][C:22]([NH:21][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][CH2:10][C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)=[CH:23][CH:24]=2)[NH:29][C:28](=[O:32])[CH2:27]1
Reactant: CC1(C)CC(=O)Nc2cc(N)ccc21
Reactant: O=C(O)c1ccccc1NCc1c[nH]c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(=O)Nc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-benzoic acid (Step A, Example 113) (200 mg), 7-amino-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (143 mg), TBTU (265 mg), and DIEA (0.14 mL) in DMF (2 mL) was stirred at RT under N2 atmosphere for 16 h. The mixture was diluted with EtOAc (10 mL) and extracted with water (2×15 mL). The organic layer was dried over Na2SO4 and the crude material was purified by flash chromatography (SiO2, 5% MeOH/CH2Cl2) to afford the titled compound as a white solid. MS (ES+): 440.0 (M+H)+. Calc'd for C26H25N5O2-439.52.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:10][CH:8]2[CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]3[S:13][CH:12]=[CH:11][C:7]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CCN1CCc2sccc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CCN1CCc2sccc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 45) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[CH3:30][O:31]C1C=C(B(O)O)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:31][CH3:30])[CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Reactant: COc1cccc(B(O)O)c1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: COc1cccc(-c2ccc(Br)cc2S(C)(=O)=O)c1
Yield: 74 %

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 3-methoxyphenylboronic acid, the title compound was obtained as a brown sticky solid in 74% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=O.[O:26]1CCOC[CH2:27]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[O:26][CH3:27])=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC=C(c1ccc(OC)cc1)c1cc(Br)cnc1N
Reactant: C1COCCO1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Temperature: 100 °C
Yield: 82 %

Procedure:
A 50 ml round bottomed flask was charged with 403 mg of 5-bromo-3-[2-methoxy-1-(4-methoxy-phenyl)-vinyl]-pyridin-2-ylamine (1.2 mmol; combined E- and Z-isomers), 1,4-dioxane (5 ml), and 70% aqueous perchloric acid (250 μl). The flask was fitted with a reflux condenser and nitrogen inlet adapter and heated in an oil bath to 100° C. for 8 hours. The reaction mixture was concentrated, then treated with 15 ml of a saturated aqueous solution of sodium bicarbonate followed by ethyl acetate (20 ml). The layers were separated, and the aqueous fraction was extracted twice with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was triturated with ether to afford 300 mg (82%) of 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a tan powder. 1H-NMR (d6-DMSO) δ=12.16 (br. s, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 7.36 (t, 1H), 7.19 (d, 1H), 7.10 (t, 1H), 3.88 (s, 3H); MS m/z: 303 [MH]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@@H]1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH2:28][C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC[C@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-pyrrolidin-2-ylmethanol and isolated as light-yellow gum (14.2 mg, 75%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1)(=[O:4])[CH:2]=[CH2:3].[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([O:25]CC)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[CH3:29][C:30](N(C)C)=O.C1C([N+]([O-])=O)=CC=C(O)C=1>C(OCC)C>[C:16]1([CH3:28])[CH:17]=[CH:18][C:19]([S:22]([O-:25])(=[O:23])=[O:24])=[CH:20][CH:21]=1.[CH2:29]([N+:11]1[C:10]2[CH:15]=[C:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:7]=[CH:8][C:9]=2[O:13][C:12]=1[CH3:14])[CH3:30]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)N(C)C
Reactant: C=CC(=O)Nc1ccc2oc(C)nc2c1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOCC
Product: C=CC(=O)Nc1ccc2oc(C)[n+](CC)c2c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
About 100 parts of (3) are combined with about 109 parts of ethyl p-toluene sulfonate, 100 ml dimethylacetamide, and 5 ml p-nitrophenol (to inhibit polymerization) in a 500 ml three-necked flask equipped with a mechanical stirrer and condenser. The reaction mixture is heated at about 120° C. for about 5 hours while stirring under argon, then stirred at room temperature for about 15 hours, monitored using thin layer chromatography (TLC). After the reaction mixture is cooled to room temperature, it is poured into about 1500 ml of dry ethyl ether, decanted and stirred in fresh ethyl ether. The ethyl ether procedure is repeated until the oil product changes to a tacky solid which is then allowed to stand in ethyl ether overnight. The solid is filtered off and washed several times with butyronitrile to remove all starting material. The solid is washed further with ethyl ether and dried to yield 3-ethyl-5-acrylamido-2-methylbenzoxazolium p-toluene sulfonate (4) as a mustard-yellow solid.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:12]1([C:18]2[CH:19]=[C:20]([C:24]([OH:26])=O)[CH:21]=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl.C(N(CC)CC)C>[C:41]1([C:39]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[C:28]([NH:27][C:24]([C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:19]=3)=[O:26])[CH:40]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)c1cncc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide (0.9 μL) and oxalyl chloride (0.023 mL) were added to a methylene chloride (0.5 mL) suspension of 5-phenylpyridine-3-carboxylic acid (44 mg) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was added to a solution mixture of tert-butyl 2-amino-4-phenylbenzoate (40 mg) in methylene chloride (1 mL) and triethylamine (0.17 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and a 10% aqueous solution of citric acid were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Trikonex AB, FlashTube 2008, eluent: hexane/ethyl acetate=2:1] to obtain tert-butyl 4-phenyl-2-(5-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1>[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:4][CH2:3][O:2][CH3:1])(=[O:6])=[O:7])=[N:9]1)=[O:24])[CH3:21]
Reactant: COCCS(=O)(=O)c1nc[nH]n1
Reactant: CCN(C(=O)Cl)C(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(=O)n1cnc(S(=O)(=O)CCOC)n1)C(C)C

Procedure:
A solution of 0.03 mole of 3-(2-methoxyethylsulphonyl)-1,2,4-triazole, 6 ml. of triethylamine and 0.033 mole of N-ethyl-N-isopropylcarbamoyl chloride in 40 ml. of dry tetrahydrofuran was heated under reflux for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The product crystallized on cooling and treatment with 100 ml. of petroleum ether (b.p. 62°-68° C.). Thin solid was collected and recrystallized from 100 ml. benzene petroleum ether (b.p. 40°-60° C.) to give 1-(N-ethyl-N-isopropylcarbamoyl)-3-(2-methoxyethylsulphonyl)-1,2,4-triazole, m.p. 64°-65° C. Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=1.Br[CH2:27][C:28]1[CH:37]=[N:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>C(#N)C>[Br-:10].[CH:13]1[C:14]2[C:23](=[CH:22][C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[CH:25][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:27][C:28]2[CH:37]=[N:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH:4]=1
Reactant: BrCc1cnc2ccccc2n1
Reactant: BrCc1ccc2cc3ccccc3cc2c1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2ccc3cc4ccccc4cc3c2)cn1Cc1cnc2ccccc2n1
Product: [Br-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)anthracene (2.71 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. 2-(Bromomethyl)quinoxaline (2.23 g, 10.0 mmol) will be added to the filtrate and the mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure to yield the product.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([CH3:16])[CH:4]=1.[C:17](O)(=O)[CH3:18].Br>C(O)C>[CH2:17]([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][C:5]=1[CH3:16])=[O:15])[CH3:18]
Reactant: COc1ccc(C(=O)CCC(=O)O)c(C)c1
Reactant: CC(=O)O
Agent: Br
Solvent: CCO
Product: CCOC(=O)CCC(=O)c1ccc(O)cc1C
Temperature: 130 °C
Yield: 75 %

Procedure:
A mixture of 4-(4-methoxy-2-methyl-phenyl)-4-oxo-butyric acid (2 g, 9 mmol), acetic acid (30 mL) and 48% aqueous HBr (10 mL) was heated at 130° C. for 5.5 h. The reaction was cooled to rt and concentrated at reduced pressure and azeotrope twice with benzene to give a crude residue. The crude residue was dissolved in ethanol (25 mL) and added amberlyst then heated at 90° C. for 18 h. The reaction was filtered over celite and evaporated ethanol at reduced pressure then quenched with water and extracted twice with methylene chloride to obtain 4-(4-hydroxy-2-methyl-phenyl)-4-oxo-butyric acid ethyl ester (1.6 g, 75%). The crude material was used for the next reaction without purification.
Reaction SMILES: OO.[NH2:3][C:4]1[CH:11]=[C:10]([N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:25]4[NH:29][C:28]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:27]=5[N:26]=4)[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].CS(C)=[O:37].[OH-].[Na+]>C(O)C.O>[NH2:3][C:4]1[CH:11]=[C:10]([N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:25]4[NH:29][C:28]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:27]=5[N:26]=4)[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:8][C:5]=1[C:6]([NH2:7])=[O:37]
Reactant: CS(C)=O
Reactant: N#Cc1ccc(-n2c3ccccc3c3c(-c4nc5ccc(F)cc5[nH]4)cccc32)cc1N
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(-n2c3ccccc3c3c(-c4nc5ccc(F)cc5[nH]4)cccc32)cc1N

Procedure:
In a 50 ml round-bottomed flask, 0.2 ml of 30% aqueous hydrogen peroxide is added to a mixture of 40 mg of 2-amino-4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]benzonitrile, obtained in the preceding stage, in 1.0 ml of ethanol and 0.4 ml of dimethyl sulphoxide and 0.2 ml of 1M sodium hydroxide, and the mixture is stirred for ¼ hour at ambient temperature. 20 ml of distilled water are added and the mixture is extracted with 3 times 30 ml of ethyl acetate. The combined organic phases are washed with 30 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and methanol (95/5 by volume). 24 mg of 2-amino-4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]benzamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: C([O:3][P:4](Cl)[O:5][CH2:6][CH3:7])C.C([Mg]Cl)[C:10]1[CH:15]=[CH:14]C=[CH:12][CH:11]=1.O.Cl.[CH2:20](OCC)C>>[CH3:20][PH:4](=[O:3])[O:5][CH2:6][C:7]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: CCOP(Cl)OCC
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: O
Product: C[PH](=O)OCc1ccccc1
Reaction time: 1 h
Yield: 32 %

Procedure:
Diethylchlorophosphite (25 g, 0.16 mol) in 100 mL of dry diethyl ether was cooled to 0° C. under an atmosphere of nitrogen. Benzylmagnesium chloride (80 mL, 0.16 mol, 2.0 M solution in Et2O) was added dropwise over two hours while maintaining a temperature below 10° C. A thick white slurry formed and stirring was continued at room temperature for 1 hour. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 ml concentrated hydrochloric acid. An exothermic reaction was observed and stirring was continued for an additional 30 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear light golden liquid was added to sodium hydroxide (50 mL, 2.0 M NaOH), stirred for 1 hour and washes with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined dried (MgSO4) and evaporated to give benzylphosphinic acid (1, R=CH2Ph, R1=H) (8 g, 32%) as a clear light golden oil.
Reaction SMILES: [I-].C1([C:8]([PH3+])([C:15]2[CH:20]=C[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(C)(C)C.[K+].[C:28]([N:35]1CCCC(=O)C1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:18][CH2:17][CH2:16][C:15](=[CH2:20])[CH2:8]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 70.7 %

Procedure:
To a mixture of triphenylmethylphosphonium iodide (22.14 g) in toluene (135 ml) was added potassium tert-butanolate (5.32 g). The solution turned to orange. Then N-Boc-3-piperidone (6.0 g) in toluene (66 ml) was dropped into the solution under argon, at 30° C. The reaction was filtered and washed with water (200 ml, 2×) and then diluted by HCl (1M), dried with anhydrous sodium sulfate. The solution was purified by flash chromatography (silica gel, PE:EA=15:1) to obtain N-Boc-3-methylenepiperidine as an oil (4.2 g).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]2[N:32]=[C:31]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH:30]=[CH:29][N:28]=2)[CH:17]=[C:18]([O:24][CH3:25])[C:19]=1[O:20][CH2:21][CH2:22]O.C1(C)C=CC(S([Cl:51])(=O)=O)=CC=1.[ClH:53].[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56]C=1>O>[ClH:51].[ClH:53].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]2[N:32]=[C:31]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH:30]=[CH:29][N:28]=2)[CH:17]=[C:18]([O:24][CH3:25])[C:19]=1[O:20][CH2:21][CH2:22][N:54]1[CH2:56][CH2:57][CH2:58][CH2:59]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(Sc2ccnc(Nc3cc(OC)c(OCCO)c(OC)c3)n2)c1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Solvent: O
Product: COc1cccc(Sc2ccnc(Nc3cc(OC)c(OCCN4CCCC4)c(OC)c3)n2)c1

Procedure:
The tosylate used as starting material was prepared by treating a solution of N-[3,5-dimethoxy-4-(2-hydroxyethoxy)phenyl]-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine (2.0 g, 4.3 mmol) in pyridine (6 ml) with p-toluenesulphonyl chloride (3.28 g, 17.2 mmol) at room temperature for 2 h. Water (25 ml) was added to the reaction followed by acidification with 2M hydrochloric acid, and this was extracted with ethyl acetate (100 ml). The organic phase was washed with 2M hydrochloric acid (100 ml) and saturated aqueous Na2CO3 (100 ml), dried (MgSO4) and concentrated under reduced pressure to give the desired product as a light brown oil (2.31 g). δH (CDCl3) 8.04 (1H, d, J 5.4 Hz), 7.80 (2H, d, J 8.3 Hz), 7.39-7.30 (3H, s), 7.20-7.13 (2H, m), 7.03-6.99 (2H, m), 6.86 (2H, s), 6.22 (1H, d, J 5.4 Hz), 4.31 (2H, t, J 5.6 Hz), 4.13 (2H, t, J 5.6 Hz), 3.81 (3H, s), 3.77 (6H, s) and 2.43 (3H, s).
Reaction SMILES: CCO[CH2:4][CH3:5].[ClH:6].[NH2:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14]>CO>[Cl:6][C:8]1[CH:9]=[CH:10][C:4]([C:5]2[O:14][C:13]3[CH:12]=[CH:11][C:10]([CH2:15][C:16]([OH:18])=[O:17])=[CH:9][C:8]=3[N:7]=2)=[CH:12][CH:13]=1
Reactant: CCOCC
Reactant: Nc1cc(CC(=O)O)ccc1O
Reactant: Cl
Solvent: CO
Product: O=C(O)Cc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reaction time: 8 h

Procedure:
A suspension of p-chlorobenzimidoethyl ether hydrochloride (16.5 g.) and 3-amino-4-hydroxyphenylacetic acid (12.53g.)in methanol (75 ml.) was refluxed for 2 hours. After standing at room temperature overnight the white solid product was removed by filtration. Re-crystallisation from ethanol gave the required acid, m.p. 241° - 242° C.