Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O>CO>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH3:18])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][CH2:34][C:30]2[NH:29][CH:33]=[CH:32][N:31]=2)=[CH:24][CH:25]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CN)cc1)C(=O)OC(C)(C)C
Solvent: CO
Product: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 107.5 %

Procedure:
The compound (0.78 g) obtained in Example 25-4 was dissolved in methanol (20 ml) and added with 2-imidazole carboxaldehyde (214.6 mg), followed by stirring at room temperature for 17 hours. After the solvent had been distilled off, the residue was dried under vacuum and then dissolved in methanol (15 ml) and then added with sodium borohydride (217.8 mg), followed by stirring at room temperature for 45 minutes. The reaction solution was added with a saturated aqueous ammonium chloride solution (10 ml) and stirred at room temperature for 15 minutes. Then, the reaction solution was added with saturated saline solution and extracted with chloroform, followed by drying with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.01 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([O:35][NH:36][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NOCc1ccccc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2Cc3ccccc3C2=O)ccc1OC
Yield: 75.1 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (1.78 g, 5.00 mmol), N,N′-carbonyldiimidazole (850 mg, 5.24 mmol) and O-benzylhydroxylamine hydrochloride (940 mg, 5.89 mmol) in tetrahydrofuran (10 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide as a white solid (1.73 g, 75% yield): mp, 132.0-133.0° C.; 1H NMR (DMSO-d6) δ1.29 (t, J=6.9 Hz, 3H, CH3), 2.83 (d, J=7.8 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.93-4.02 (m, 2H, CH2), 4.09 (d, J=17.5 Hz, 1H, NCHH), 4.51 (d, J=17.5 Hz, 1H, NCHH), 4.59 (d, J=11.3 Hz, 1H, PhCHH), 4.66 (d, J=11.2 Hz, 1H, PhCHH), 5.74 (t, J=7.8 Hz, 1H, NCH), 6.83-6.93 (m, 3H, Ar), 7.21-7.29 & 7.45-7.59 (m, 8H, Ar), 7.68 (d, J=7.4 Hz, 1H, Ar), 11.17 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.66, 35.08, 46.18, 51.29, 55.43, 63.71, 76.69, 111.82, 112.11, 119.25, 122.82, 123.44, 127.85, 128.17, 128.75, 131.31, 131.61, 132.17, 135.86, 141.68, 147.88, 148.45, 166.26, 166.88. Anal. Calcd for C27H28N2O5: C, 70.42; H, 6.13; N, 6.08. Found: C, 70.31; H, 6.07; N, 5.88.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:23](Cl)(=[O:25])=[O:24])([CH3:13])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:23]([C:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[S:18][C:14]=1[CH:11]([CH3:13])[CH3:12])(=[O:24])=[O:25]
Reactant: CC(C)c1sc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(C(C)C)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 9.7 mg), NaH (1.4 mmoles, 5.5 mg), 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride (0.60 mmoles, 0.17 g) and THF (2 ml). Recrystallization from chloroform and hexanes provided 89 mg (39%) of a tan crystalline solid, m.p. 157.5°-159° C.
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(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[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]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)S(=O)(=O)c3ccc(Cl)cc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)S(=O)(=O)c3ccc(Cl)cc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-6-(N-4-chlorobenzenesulphonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:26])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][N:14]=1)[CH2:6][CH2:5]2.[CH2:27]([CH:30]1[O:32][CH:31]1[CH2:33]O)[CH2:28][CH3:29]>>[F:1][C:2]1[C:3]([O:26][CH2:33][CH:31]2[CH:30]([CH2:27][CH2:28][CH3:29])[O:32]2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][N:18]=1)[CH2:6][CH2:5]2
Reactant: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3O)C2)nc1
Reactant: CCCC1OC1CO
Product: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3OCC3OC3CCC)C2)nc1

Procedure:
From 6,7-difluoro-2-(5-hexyloxypyrimidin-2-yl)-5-hydroxy-1,2,3,4-tetrahydronaphthalene and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36]>>[CH:35]([NH:38][C:39]([N:11]1[CH2:12][CH2:13][C:14]2[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:3]=3[F:2])[N:7]=[C:8]([C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([C:18]#[N:19])[CH:16]=3)[C:9]=2[CH2:10]1)=[O:40])([CH3:37])[CH3:36]
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
To a mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.060 g, 0.171 mmol) and triethylamine (138 mg, 1.37 mmol) at 0° C. was added isopropylisocyanate (17.5 mg, 0.21 mmol) and the mixture was stirred at room temperature for 16 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic) to give 19 mg of 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide (11a).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][CH2:40][C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40](=[CH:11][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[C:21]([F:24])([F:22])[F:23])[N:3]=[C:2]4[Cl:1])[C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(Cl)nn4Cc3ccc(Cl)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 5-chloroindole (3.0 g, 20 mmol) and 4-piperidone hydrochloride hydrate (6.0 g, 40 mmol). The product was isolated as a yellow solid. Yield 1.45 g (31%). mp 185°-188° C. FDMS m/e=234 (M+ of free base).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.S(=O)(=O)(O)O.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:15])=[O:8])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cs1
Temperature: 50 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (25 g, 121 mmol) in methanol (241 ml) was added sulfuric acid (32 ml, 604 mmol). The resulting solution stirred at 50° C. over 4 d. The solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-2-thiophenecarboxylate (26 g, 118 mmol, 97% yield), LCMS (ES) m/e 222 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Cl.[OH-].[Na+].O>CO>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: C1=Cc2ccccc2C1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCCC1=CCc2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 232 g. (2.0 moles) of indene and the free base prepared from 264 g. (1.6 moles) of 3-dimethylaminopropylchloride-hydrochloride is added in portions over 1 hour to a rapidly stirred mixture of 300 g. (7.5 moles) of sodium hydroxide, 300 g. of water and 300 ml. of 40% Triton B in methanol. The initial temperature is 50° and the rate of addition controlled to keep the temperature between 55°-60°. The green mixture is stirred at 60° for 4 hours, cooled, diluted with 1500 ml. of water and extracted with ether. The ether extract is in turn extracted with a solution of 180 ml. of conc. hydrochloric acid in 600 ml. of water and the aqueous phase separated, basified with 100 g. of sodium hydroxide and extracted with ether. Solvent removal gives 182 g. of brown oil which is distilled to give 102 g. of oil, b.p. 88°-93 ° at 0.05 mm. Redistillation gives 19.6 g; b.p. 87.5°-89.5° at 0.05 mm. and 71.1 g., b.p. 89.5°-90° at 0.05 mm.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=1)=[O:10])(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][CH:8]([CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound E in DCM (4 mL) is added TFA (4 mL) at 0° C. The solution is stirred at room temperature for 1 hr and dried under vacuum. The crude oil is used directly in the next step without further purification. M+H+=369.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=[C:7]2[CH2:6][C:5]1=[O:16]>C(O)(=O)C>[Br:1][CH2:14][C:13]([C:11]1[CH:12]=[C:7]2[CH2:6][C:5](=[O:16])[N:4]([CH3:3])[C:8]2=[N:9][CH:10]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1cnc2c(c1)CC(=O)N2C
Solvent: CC(=O)O
Product: CN1C(=O)Cc2cc(C(=O)CBr)cnc21
Temperature: 80 °C
Yield: 60 %

Procedure:
Add 170 mg (1.05 mmol) of bromine dissolved in 1 ml of acetic acid dropwise to a solution of 200 mg (1.05 mmol) of 1,3-dihydro-1-methyl-5-acetyl-2H-pyrrolo[2,3-b]pyridin-2-one (obtained as described in Example 13 hereinafter) in 4 ml of acetic acid. After 6 hours' heating at 80° C., the acetic acid is removed under reduced pressure and the residue is taken up in water and then extracted with dichloromethane. The crude product obtained is purified by chromatography on silica gel (eluant ethyl acetate/petroleum ether/dichloromethane, 1/1/1). Yield: 60%. ##STR43##
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N:13]([CH3:15])[CH3:14].Br[CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N:13]([CH3:14])[CH3:15]
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)c(N(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCCCl)c(N(C)C)c1
Temperature: 3 °C
Reaction time: 0.75 h
Yield: 179 %

Procedure:
To a suspension of sodium hydride (2.3 g, 48.5 mmol of 50% oil dispersion) with dimethylformamide (75 ml), and cooled to 3° C. in an ice-salt bath and under a stream of nitrogen was added, dropwise, 1-(4-hydroxy-3-dimethylaminophenyl)ethanone (8.7 g, 48.5 mmol) dissolved in dimethylformamide (150 ml) so that the temperature did not go over 7° C. After the addition was over, the bath was removed and the reaction was stirred at ambient temperature for 45 minutes. The ice bath was reapplied and a solution of 1-bromo-3-chloropropane (8.4 g, 53.4 mmol) in dimethylformamide (25 ml) was added dropwise. After the addition was complete, the reaction was stirred for 18 hours at ambient temperature under nitrogen. The reaction was chilled to 7° C. in an ice bath and water (200 ml) was carefully added. After stirring for 5 minutes, the aqueous mixture was extracted with ethyl acetate (5×200 ml). The ethyl acetate extract was washed with water (2×50 ml), dried with MgSO4, and concentrated to yield 22.2 g of a black oily liquid. The compound was purified by prep HPLC, and combination of appropriate fractions gave 5.0 g of brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][C:5]([CH:8]([CH3:11])[CH:9]=[O:10])=[C:4]2[C:12]([CH3:18])([CH3:17])[CH:13]3[CH2:16][C:3]12[CH2:15][CH2:14]3.[CH3:20][Mg]Br>C(OCC)C>[CH3:19][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([CH:8]([CH3:11])[CH:9]([OH:10])[CH3:20])=[C:4]2[C:12]([CH3:18])([CH3:17])[CH:13]3[CH2:16][C:3]12[CH2:15][CH2:14]3
Reactant: C[Mg]Br
Reactant: CC(C=O)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Solvent: CCOCC
Product: CC(O)C(C)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
9b (1.7 g, 6.5×10−3 mol) in diethyl ether (50 ml) was added dropwise at 10° C. to a solution of methylmagnesium bromide (3 ml of 3M diethyl ether solution, 9.0×10−3 mol) in the same solvent (50 ml). The reaction mixture was stirred at r. t. for additional 2 h, poured into ice-cold 0.1M HCl (100 ml) and extracted with MTBE (100 ml). The organic phase was washed with brine (2×50 ml), dried (MgSO4), concentrated in vacuo and purified by recrystallisation from hexane to afford 3-(2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undec-5-en-5y-1)butan-2-ol (10b, 1.1 g, 61% yield, white prisms, m.p. 119-121° C.).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18][C:19]([OH:21])=[O:20])[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:33](=[O:36])([O-])[O-:34].[Na+].[Na+]>C1C=CC=CC=1>[C:33]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:20][C:19](=[O:21])[CH2:18][C:10]1[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:34])=[O:36]
Reactant: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)Oc1ccccc1C(=O)O
Reaction time: 0.42 h
Yield: 54 %

Procedure:
7.0 grams 1,3,5-triphenyl-pyrazol-4-acetic acid, 3.1 grams phosphorus oxychloride and 40 milliliters benzene were mixed and the mixture was heated to the boiling temperature under reflux for 2 hours. The reaction mixture was then poured on ice, the pH adjusted to 6 by the addition of dilute aqueous sodium carbonate solution. The benzene solution was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue, consisting of 1,3,5-triphenyl-pyrazol-4-acetylchloride was taken up in 40 milliliters absolute ether. The ether solution was then added dropwise at 0°-3° C. and within 20 minutes to a solution of 2.8 grams salicyclic acid in a mixture of 20 milliliters ether and 4.2 grams pyridine. The mixture was after stirred for 25 minutes and thereafter poured on a mixture of ice and concentrated aqueous hydrochloric acid. The acid solution was separated, extracted with water, and the ether evaporated. The residue was recrystallized from ethanol. 5.1 grams 1,3,5-triphenyl-pyrazol-4-acetic acid-(2-carboxyphenyl)-ester, melting at 190°-191° C., were obtained representing a yield of 54%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]([CH2:25][C:26]3[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cn2c(N3CCCN(C(=O)OCC)CC3)nc3ccccc32)o1
Reaction time: 72 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol) and sodium hydride (10 mmol) in dimethylformamide (20 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (10 mmol) and stir. After 3 days, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([C:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([C:31]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH:32]=3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: OC1CC=C(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OC1CC=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 200 °C
Yield: 6.3 %

Procedure:
To a vial containing cesium carbonate (1391 mg, 4.27 mmol) was added 4-(benzo[d]thiazol-2-ylamino)phenol (1035 mg, 4.27 mmol), and 4-(2-fluoropyridin-3-yl)cyclohex-3-enol (330 mg, 1.708 mmol) followed by NMP (2.2 mL). The reaction was heated at 200° C. for 2 h with microwave irradiation. The black mixture was diluted with ethyl acetate and washed with 5N NaOH before drying over sodium sulfate, filtering, and concentrating under reduced pressure to a brown residue. Purification by column chromatography (ethyl acetate/dichlormethane) afforded 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)cyclohex-3-enol (44.8 mg, 0.108 mmol, 3, steps, 6.31% yield) as a pale brown oil. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][CH:29]=[C:30]([O:32]C)[CH:31]=1)[N:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2].C(S)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][CH:29]=[C:30]([OH:32])[CH:31]=1)[N:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cncc(OC)c1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](c1cncc(O)c1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 16-3 (200 mg, 0.4278 mmol) and ethanethiol (0.5 ml) and CH2Cl2 (3 ml) was added AlCl3 (570 mg, 4.28 mmol). After 1.0 hour, the reaction was quenched with sat. NaHCO3. Ethyl acetate was added, and the reaction mixture was then purged with argon for 1.0 hour. The organic layer was separated, washed with brine, dried (MgSO4) and then concentrated to give the phenol 16-4 as a yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]2)OCC1.Br[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([Br:31])=[CH:26][N:25]=1>O>[Br:31][C:27]1[CH:28]=[C:29]([CH3:30])[C:24]([C:18]2([C:21]#[N:22])[CH2:17][CH2:16][C:15](=[O:11])[CH2:20][CH2:19]2)=[N:25][CH:26]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1C1(C#N)CCC(=O)CC1
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
1M Solution of sodium bis(trimethylsilyl)amide (77 ml) was added under ice cooling to 1,4-dioxaspiro[4,5]decane-8-carbonitrile (11.0 g) described in Reference Example 82(1) and stirred for 30 minutes. Then, 2,5-dibromo-3-methylpyridine (15 g) was added, stirred for 30 minutes and further stirred at room temperature for an hour. The reaction solution was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated in vacuo. To the residue, were added trifluoroacetic acid (20 ml) and water (5 ml), and the mixture was stirred at 40° C. for two hours. The reaction solution was treated with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue was purified with silica gel column chromatography (ethyl acetate:n-hexane=5:1) to give 1-(5-bromo-3-methylpyridin-2-yl)-4-oxocyclohexanecarbonitrile (17.1 g).