Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.[CH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:28]=1)=[O:26]>C1COCC1>[C:15]([O:14][C:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])[CH:28]=2)[OH:26])=[CH:3][CH:4]=1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C=O)ccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(O)c2ccc(NC(=O)OC(C)(C)C)c3ccccc23)ccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl (4-bromonaphthalen-1-yl)carbamate (WO 2006/010082) (2.09 g, 6.48 mmol) in dry THF (50 mL) under N2 at −78° C. was added n-butyllithium (2.5 M in hexanes, 5.5 mL, 13.8 mmol) over 15 mins. The resulting mixture was maintained at −78° C. for 1.5 hr and then treated with a solution of tert-butyl (4-formylpyridin-2-yl)carbamate (WO 2004/000831) (960 mg, 4.30 mmol) in dry THF (10 mL) in one portion. The reaction mixture was stirred at −78° C. for a further 1 hr and then warmed to RT for 18 hr. The mixture was cooled to 0° C. and the reaction was quenched by the addition of MeOH (5.0 mL), then warmed to RT and partitioned between EtOAc and water. The aq layer was separated and was extracted twice with EtOAc and the combined organic extracts were washed with brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 0-60%, gradient elution) to afford the title compound, Intermediate F1, as a pale yellow solid (1.13 g, 88% purity (LCMS), 49%); Rt 2.22 min (Method 2); m/z 466 (M+H)+ (ES+). The material so obtained was used in the next step without further purification.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@@H:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=O)=O)=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1)#[N:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[C:32]([C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[CH:44][C:43]([O:10][CH2:11][C@@H:12]([OH:21])[CH2:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1)#[N:33]
Reactant: N#Cc1cccc(-c2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(-c2ccc(OC[C@@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Prepared according to the method described in Example 26e) from (2S)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.46 g, Example 26d)), sodium hydride (60%, 0.056 g) and 4-(3-cyanophenyl)phenol (0.273 g) in dimethylformamide (5 ml). The adduct was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride (0.522 g) was added. The reaction was stirred at ambient temperature for 1 hour and was then poured into brine and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a solid (0.22 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc(-c2cn(-c3cccs3)cn2)cc1
Temperature: 110 °C
Yield: 2.9 %

Procedure:
A suspension of 4-phenyl-1H-imidazole (500 mg, 3.47 mmol), 2-bromothiophene (0.4 ml, 4.16 mmol), CuI (131.9 mg, 0.694 mmol, trans-N,N′-dimethylcyclohexanediamine (0.08 ml, 0.694 mmol), and K2CO3 (1.43 g, 10.4 mmol) in dioxane (5 ml) was heated at 110° C. in a sealed tube for 16 hours. The reaction mixture was then diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography using 15-20% ethyl acetate/hexanes to yield the desired 4-phenyl-1-(thiophen-2-yl)-1H-imidazole (23 mg, 3%). The HPLC purity of the final product was 99.7%. LC-MS [M+H] 227 (C13H10N2S+H expected 227.06).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[C:19]=2[N:18]=[C:17]1[CH2:27][O:28][CH2:29][CH3:30]>>[NH2:26][C:20]1[C:19]2[N:18]=[C:17]([CH2:27][O:28][CH2:29][CH3:30])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[S:10])[C:24]=2[CH:23]=[C:22]([CH3:25])[N:21]=1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Reactant: O=C(N=C=S)c1ccco1
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=S)NC(=O)c1ccco1

Procedure:
Using the method of Examples 36-45, 2-furoylisothiocyanate was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 431.887.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:33])([F:32])[C:28](OC)=[O:29].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:28](=[O:29])[C:27]([F:33])([F:32])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: COC(=O)C(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (4.62 g) in tetrahydrofuran (100 ml) at -75° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -75° C., n-butyllithium (4.7 ml of a 2.5M solution in hexanes). A solution of methyl trifluoroacetate (1.93 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture was allowed to warm to room temperature. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (80 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a brown gum which was purified by column chromatography on silica gel (250 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 124-125° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.[NH2:23][C:24]([NH2:26])=[NH:25]>>[CH:10]1([C:9]2[N:8]([C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[N:7]=[CH:6][C:5]=2[C:3]([NH:25][C:24]([NH2:26])=[NH:23])=[O:2])[CH2:11][CH2:12]1
Reactant: N=C(N)N
Reactant: COC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
coupling said 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[CH:6][C:5]=1[OH:13])[CH2:2][CH3:3].I[CH3:15].[H-].[Na+]>CN(C=O)C>[CH3:15][O:13][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][CH3:12])[CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1ccc(CCC)c(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(CCC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
To a solution of 2,5-dipropylphenol (3.50 g, 19.6 mmol) and iodomethane (3.70 mL, 58.8 mmol) in DMF (65 mL) at 0° C. was added sodium hydride (1.60 g, 39.2 mmol, 60% dispersion in oil) in two portions. The resulting mixture was stirred at 0° C. for 10 min and then at room temperature for 14 h. After being quenched with water, the mixture was extracted in hexanes (3×100 mL) with 50% saturated brine (50 mL). Flash chromatography with silica gel (100% hexanes) afforded the title compound as a colorless liquid (3.70 g, 97% yield): 1H NMR (300 MHz, CDCl3) δ 0.95 (two overlapping triplets, 6H), 1.60 (m, 4H), 2.55 (m, 4H), 3.81 (s, 3H), 6.66 (s, 1H), 6.70 (d, 1H, J=7.5 Hz), 7.02 (d, 1H, J=7.5 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)=[O:42]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC(=O)C(C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with pivaloyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[3-(2,2-dimethyl-propionyloxy)-propoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 576 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH2:10][S:9][N:8]=[C:7]([N:12](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH2:3]1.ClCCl.Cl>O1CCOCC1.CO>[NH2:12][C:7]1[C:6]2[C:5]3[C:4](=[N:29][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:27]=2)[CH2:3][CH:2]([OH:1])[C:11]=3[CH2:10][S:9][N:8]=1
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N)=NSC4)c1C
Yield: 48.1 %

Procedure:
A mixture composed of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (40 mg), dichloromethane (1 mL), a 4 N solution of hydrochloric acid in dioxane (0.5 mL) and methanol (0.5 mL) was stirred at room temperature for two days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (12.5 mg, 48%) as a solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26](Cl)=[C:21]3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C>C(O)C>[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]([NH:2][CH:3]4[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]4)=[C:21]3[CH:20]=[CH:19]2)(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1CCC(O)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
A mixture of 3-Amino-cyclopentanol hydrochloride (0.9 g, 5.9 mmol), 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.0 g, 5.9 mmol) and diisopropylethylamine (2.3 g, 17.7 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 hours. The reaction mixture was purified by column chromatography (Hexanes/ethyl acetate=3:1) to give 2.6 g (76%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol; 1H NMR (400 MHz, CDCl3) δ: 9.56 (s, 1H), 9.54 (s, 1H), 8.19-8.16 (m, 2H), 7.62-7.56 (m, 4H), 6.82-6.81 (m, 1H), 4.56-4.50 (m, 2H), 2.25-1.96 (m, 6H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].C([Li])CCC.[CH3:30][C:31]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[CH:42][C:41]=1[O:48][CH3:49])=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH3:30][C:31]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]=[CH:2][CH:3]([CH3:5])[CH3:4])=[CH:42][C:41]=1[O:48][CH3:49])=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)C=C(C)COc1ccc(C=O)cc1OC
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CCOC(=O)C=C(C)COc1ccc(C=CC(C)C)cc1OC

Procedure:
Following the above procedures, isobutyltriphenylphosphonium bromide (9.60 g, 24.0 mmol), n-butyllithium (9.0 mmol) and ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2butenoate (1.67 g, 6.0 mmol) are reacted together to give ethyl 3-methyl-4-[2-methoxy-4-(3-methyl-1-butenyl)phenoxy]2-butenoate, MS m/e 318 (M+).
Reaction SMILES: FC1C(O)=CC=C(F)C=1C(OC)C(O)=O.[C:16]([C:18]1[CH:40]=[CH:39][C:21]([CH2:22][NH:23][C:24](=[O:38])[CH:25]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[C:31]([OH:36])[C:30]=2[F:37])[O:26][CH2:27]C)=[CH:20][CH:19]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:24](=[O:38])[CH:25]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[C:31]([OH:36])[C:30]=2[F:37])[O:26][CH3:27])=[CH:39][CH:40]=1)#[N:17]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Agent: COC(C(=O)O)c1c(F)ccc(O)c1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F

Procedure:
(RS)-N-(4-Cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-methoxy-acetamide was prepared from (RS)-(2,6-difluoro-3-hydroxy-phenyl)-methoxy-acetic acid in analogy to (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetamide (example 213). White foam. MS 330.8 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([NH:14][NH2:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)#[N:17].C[O-].[Na+].CO>C(OCCO)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)NN)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCCO
Product: CC(C)(C)OC(=O)N1CC(c2n[nH]c(-c3ccccn3)n2)C1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
3-hydrazinocarbonyl-azetidine-1-carboxylic acid tert-butyl ester (2.74 g, 12.73 mmol) and 2-cyano-pyridine (1.45 g, 13.95 mmol) were dissolved in 2-ethoxyethanol (30 mL) and a 30 wt % solution of NaOMe in MeOH (1.19 mL, 6.38 mmol) was added. The resulting mixture was heated to 130° C. and stirred overnight. On cooling the mixture was neutralised by the addition of acetic acid and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase was dried (Na2SO4) and concentrated in vacuo to give a yellow solid. Further purification was achieved by trituration with diethyl ether followed by recrystallisation from MeOH.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:21](=[C:22]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:23]=1[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17]1[O:18][CH2:19][O:20][C:16]=1[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([C:22]3[C:23]([CH2:24][O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=[C:13]4[C:21]=3[C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=[CH:14]4)=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: O=C(OCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Yield: 63.7 %

Procedure:
A solution of 4 (56 mg, 0.11 mmol) and NaOH (16 mg, 0.4 mmol) in MeOH/H2O (4:1, 2 mL) was heated at 70° C. for 12 h. The solvent was evaporated to dryness, and the residue was dissolved in water. The aqueous solution was acidified to pH 1-2 with 10% aqueous HCl solution and then extracted with ether (3×50 mL). The extract was washed with water and brine, and dried over MgSO4. The evaporation of solvent yielded 5 (32 mg, 70%) as a white powder. mp 219-221° C.; 1H NMR (DMSO-d6) δ 8.27 (s, 1H, H4), 7.70 (d, 1H, H5, J=8.7 Hz), 7.38 (d, 1H, H6, J=8.7 Hz), 7.17-7.25 (m, 5H, OCH2Ph), 6.89 (d, 1H, H5′, J=8.1 Hz), 6.79 (d, 1H, H2′, J=1.5 Hz), 6.65 (dd, 1H, H6′, J=1.5, 8.1 Hz), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=18.0 Hz, J=0.6 Hz), 5.85 (AB, 2H, 7,8-OCH2O—, Δδ=9.3 Hz, J=0.9 Hz), 4.53 (s, 2H, 2-CH2OCH2Ph), 4.24 (s, 2H, 2-CH2OBn); MS (FAB, positive) m/z 457 [M+H]+.
Reaction SMILES: [N:1]1[C:2](=[O:10])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:11](Br)[C:12]#[CH:13]>CN(C)C=O>[C:12]1([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]([CH2:8][C:7]#[CH:6])[C:2]2=[O:10])[CH:13]=[CH:9][CH:4]=[CH:5][CH:11]=1
Reactant: O=C1N=c2ccccc2=N1
Reactant: C#CCBr
Solvent: CN(C)C=O
Product: C#CCn1c(=O)n(-c2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
1.76 g (15.7 mmol) was added to a solution of 3 g (14.2 mmol) of 1.3-dihydro-1-phenyl 2H. benzimidazol-2-one in 30 ml of dimethylformamide and the mixture was stirred under nitrogen for 15 minutes. propargyl bromide, 1.4 ml (15 mmol) was then added and stirring was continued for 30 minutes at room temperature and 15 minutes on the steam bath. The product was precipitated by dilution with saturated aqueous sodium bicarbonate solution and was filtered off, washed with water and sucked dry. It was dissolved in methylene chloride and the solution was passed over a plug of silica gel using methylene chloride. The filtrate was evaporated and the residue was crystallized from methylene chloride/ethyl acetate to give colorless crystals of 1.3-dihydro-1-phenyl-3-(2-propynyl)-2H-benzimidazol-2 one with m.p. 145°-147°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]>>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1
Reactant: CN1CCNCC1
Reactant: O=C1CCc2cccc(Cl)c2C1
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCNCC1C1CCc2cccc(Cl)c2C1

Procedure:
Using the method of Example 3, 0.5 g (2.78 mmol) of 8-chloro-2-tetralone was treated with N-methylpiperazine, and the resulting product was reduced with sodium borohydride and the product treated with maleic acid to obtain 0.48 g of the title compound as colorless crystals, m.p. 199°-201° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH3:15][C:16]1([CH3:40])[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]=[C:19]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)[C:18]=2[CH2:17]1>>[CH3:15][C:16]1([CH3:40])[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]=[C:19]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34]([C:2]5[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=5)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)[C:18]=2[CH2:17]1
Reactant: CNc1ncc(Br)cc1NS(C)(=O)=O
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CNc1ncc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cc1NS(C)(=O)=O

Procedure:
Prepared according to the method of example 5 by using N-[5-bromo-2-(methylamino)pyridin-3-yl]methanesulfonamide (reagent preparation 39) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.35 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 4.68 (s, 2H), 4.32 (m, 2H), 3.94 (m, 2H), 3.00 (s, 3H), 2.98 (s, 3H), 2.79 (t, 2H), 2.46 (s, 2H), 1.67 (t, 2H), 0.90 (s, 6H); MS (EI) for C26H32N6O3S: 509 (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9]CCO2)[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH2:25]C3(CCC(=O)CC3)O[N:22]=2)[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH2:25][C:5]3([CH2:4][CH2:3][C:2](=[CH2:1])[CH2:11][CH2:10]3)[O:9][N:22]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: O=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Product: C=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized using the same methodology described for Compound 31a, but starting from the compound of Example 32 instead of 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (Horizon®TM-Biotage; gradient Petroleum Ether-Acetone EtOAc from 95:5 to 9:1) to give the title compound as a grey solid. Yield: 67.3%
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1)#[N:2].[BH4-].[Na+].O>[OH-].[K+]>[OH:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: N#CC1CCC(C=O)CC1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CC1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
A solution of 1.34 g of 4-cyanocyclohexanecarboxaldehyde (cis/trans mixture) in 40 ml of 0.1N methanolic potassium hydroxide solution was treated portionwise at 0° C. under argon gasification with 378 mg of solid sodium borohydride. After completion of the addition, the mixture was stirred at 0° C. for a further 20 minutes, then 50 ml of water were added and the mixture was extracted three times with 50 ml of methylene chloride each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residual oil on silica gel with chloroform/ethyl acetate (1:1) gave 1.22 g (90%) of 4-(hydroxymethyl)cyclohexanecarbonitrile (likewise as an about 1:1 mixture of the two epimers) as a colourless viscous oil. This material was used in the following tosylation without further purification. Rf-value of 4-(hydroxymethyl)cyclohexanecarbonitrile [chloroform/ethyl acetate (1:1)]: 0.29 (longish spot).