Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25](OCC)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39].C[Al](C)C>C1COCC1>[OH:42][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@@:3]3([C:11]4[CH2:12][C:13]5[C:18]([CH:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@H:2]3[OH:1])=[CH:31][CH:30]=2)=[CH:41][C:37]=1[C:38]([OH:40])=[O:39]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Yield: 36.2 %

Procedure:
To a mixture of ethyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H, 1′H-[2,2′-biinden]-2-yl)methyl)benzoate (18, 200 mg, 0.48 mmol), 5-amino-2-hydroxybenzoic acid (75 mg, 0.48 mmol) and THF (1.0 mL) in a 5 mL microwave vial, was added trimethylaluminium (0.5 mL, 20% solution in toluene) and the mixture irradiated at 100° C. for 5 min. The reaction mixture was quenched with slow addition of 1.5 N HCl (2 mL) and extracted with ethyl acetate (3×15 mL). Organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue purified by preparative HPLC [Kromasil C18 (250×50 mm), flow rate: 40 mL/min, 0.1% TFA in water/MeOH, run time: 40 min] to yield 90 mg (36%) of the title compound as an off white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:12]([C:11]2[CH:10]=[CH:9][C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])=[CH:18][CH:17]=2)=[O:14])[CH2:31][CH2:32]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2CCCCC2=O)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCC4=O)cc3)CC2)c(C)c1
Yield: 56 %

Procedure:
Using ethyl 4-(2-oxopiperidin-1-yl)benzoate (247 mg) and 1-(2,4-dimethylphenyl)piperazine (190 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (219 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ccnc2ccccc12
Reactant: c1ccc(CN2CCNCC2)cc1
Product: c1ccc(CN2CCN(c3ccnc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
To a solution of 4-chloroquinoline (3 g) in mixed xylenes (b.p. 137°-144° C.) (25 ml) was added 1-benzylpiperazine (6.46 g). The mixture was heated to reflux with stirring for 20 hours then cooled to room temperature. The precipitate that formed was filtered and washed with xylene. To the combined filtrate and washings was added decolourising charcoal and the mixture was heated to reflux for 20 minutes, cooled and filtered through kieselguhr. The filtrate was evaporated to dryness to yield 1-benzyl-4-(4-quinolinyl)piperazine (4.55 g) as a yellow solid: m.p. 105°-106° C.; NMR (CDCl3) δ2.75 (4H, m), 3.26 (4H, m), 3.66 (2H, s), 6.84 (1H, d), 7.35 (5H, m), 7.45 (1H, m), 7.65 (1H, m), 8.03 (2H, m), 8.73 (1H, m); m/Z 304 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42](O)=[O:43])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1)=[O:43]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C1
Yield: 32 %

Procedure:
Following the procedures as described in Example 113, (R)-tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 126 as a white solid (38 mg, 32%) over two steps. 1H NMR (400 MHz, DMSO) δ 7.67 (d, J=19.5, 1H), 7.62-7.45 (m, 3H), 7.28 (t, J=8.7, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 3.20 (dt, J=8.9, 4.4, 2H), 2.84 (d, J=10.2, 2H), 2.05-1.84 (m, 2H), 1.75 (s, 2H). ESIMS m/z=420.1 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][O:7]C1CCCCO1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:17]1([C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:6][OH:7])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: Brc1cccc(CCOC2CCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: OCCc1cccc(N2CCCC2)c1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 2-(3-bromophenethoxy)tetrahydro-2H-pyran (6.27 g, 21.9 mmol) in toluene (15 ml) and pyrrolidine (2.2 ml, 26.4 mmol) were added to a mixture of dry palladium acetate (58 mg, 0.26 mmol), 2-(di-t-butylphosphino)biphenyl (136 mg, 0.46 mmol) and sodium t-butoxide (3.23 g, 33.6 mmol), and they were stirred at 70° C. for 12 hours. Water was added to the reaction mixture. After the extraction with ethyl acetate, the product was extracted from the organic layer with 1 M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was dried to quantitatively obtain 3-pyrrolidinophenethyl alcohol in the form of a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:29])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:29])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)([OH:16])[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc(C(C)C(O)(c2ccc3c(c2)N(C)C(=O)CO3)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 103.4 %

Procedure:
A solution of 6-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (4.9 g, 11.4 mmol) in dichloromethane (130 ml) was cooled to −70° C. A 1 M solution of boron tribromide in dichloromethane (45.6 ml) was added dropwise (25 min) and the mixture was stirred at −70° C. for 1.5 h. The ice bath was removed and the mixture was stirred at r.t. for 3 h. The reaction mixture was poured on a mixture of ice water and sat aq NaHCO3 solution, extracted three times with dichloromethane. The organic phases were washed with water and dried (MgSO4) and concentrated. The product was dried under high vacuum to give the title compound (4.9 g) as an off-white solid. MS (m/e)=416.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=[N:6][C:5]=2[N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:33])[NH:21][C:22]([CH3:32])=[CH:23][C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([C:24]1[CH:23]=[C:22]([CH3:32])[NH:21][C:20](=[O:33])[C:19]=1[CH2:18][NH:17][C:11]([C:9]1[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH:14]([CH3:16])[CH3:15])[C:5]=2[N:6]=[CH:7][CH:8]=1)=[O:13])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2nccc(C(=O)O)c12
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2ccnc3c2c(C)nn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for example 11 from 3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.060 g, 0.274 mmol) and 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone (0.076 g, 0.287 mmol). The product was collected as a white solid (92 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.82 Hz, 6 H), 2.09 (s, 3 H), 2.41 (s, 3 H), 3.98 (s, 2 H), 4.43 (d, J=5.05 Hz, 2 H), 5.16 (quin, J=6.63 Hz, 1 H), 5.79 (s, 1 H), 7.04 (d, J=4.80 Hz, 1 H), 7.16-7.34 (m, 5 H), 8.49 (d, J=4.55 Hz, 1 H), 8.75 (t, J=5.05 Hz, 1 H), 11.59 (s, 1 H). LCMS(ES) [M+H]+ 429.9
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: O=C(O[C@H]1CCNC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[C:7]1([CH3:14])[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:13][C:9]1[CH:8]=[C:7]([CH3:14])[CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: Cc1cccc(N)c1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NCCCl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95753.2 %

Procedure:
1-Chloro-2-isocyanato-ethane (2.36 g, 0.02239 mmol) was added dropwise to a stirred solution of m-tolylamine (2 g, 0.01866 mmol) in toluene (50 mL) over a period of 30 minutes at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (5% MeOH in DCM). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 3.8 g (97% yield) of 1-(2-chloro-ethyl)-3-m-tolyl-urea.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:20])=[CH:16][C:15]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:29]([C:15]1[CH:16]=[C:17]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[O:20])[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:33])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(F)cc2)n(-c2cccc(CCC(=O)O)c2)n1
Yield: 87.2 %

Procedure:
A solution of Example 145 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH=4, extracted with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine, dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid, (37 mg, 90%). 1H NMR (CD3OD): 7.63–7.62 (m, 2H), 7.56 (s, 1H), 7.53–7.48 (m, 1H), 7.41–7.38 (m, 2H), 7.04 (t, J=8.8 Hz, 2H), 5.49 (s, 1H), 3.07 (t, J=7.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 415 (M+H+).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][C:27](CC)=[O:28]>>[C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][C:6]2([O:28][CH2:27][CH2:26][O:9]2)[CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])#[N:2]
Reactant: CCC(C)=O
Reactant: CCCCCC1C(=O)CCC1CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCC1C(CC#N)CCC12OCCO2
Reaction time: 5 h
Yield: 73.4 %

Procedure:
Into a 2 liter flask fitted with a 1 meter adiabatic column provided with a metallic lining, are placed: 400 g of 3-cyanomethyl-2-n-pentyl-1-cyclopentanone, 522 g of the glycoketal of methylethyl ketone and 4.5 g of paratoluenesulphonic acid. The mass is progressively heated in order to slowly distil the methyl ethyl ketone from the head of the column (temperature of the mass 128°-132°C; temperature of the vapour 80°C). The operation lasts about 5 hours. Then the excess glycoketal of methylethyl ketone is removed (temperature of the mass 132°-135°C; temperature of the vapour 110°-112°C). The mass is then cooled, 30 g of dry sodium carbonate added thereto, stirred for a half-hour and the mass washed to neutrality after diluting with 200 ml of ethyl ether. After distillation of the solvent and rectification of the crude product, there is obtained 360 g of 3-cyanomethyl-1,1-ethylenedioxy-2-n-pentyl-cyclopentane, which represents a yield of 73.4%. The product exhibits the following constants: b.p.0.5 = 136°-138°C, nD15 = 1.4724.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F

Procedure:
2.11 g (0.01 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 25 ml of chlorobenzene at room temperature. 12 ml (0.02 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 10 minutes with vigorous stirring and the mixture is stirred for a further 4 hours during which the reaction temperature rises to 30° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.5 mbar, 100°-120° C. bath temperature), 1.41 g (67% of theory) of 2-chloro-5-trifluoroacetylpyridine are obtained, which, according to GC, is 98% pure.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C1CCN2C(=NCCC2)CC1.[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39]Br)([CH3:33])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:39][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:41])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1c(SCCCNC(=O)OC(C)(C)C)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A solution of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 502 mg, 1.9 mmol) and DBU (289 mg, 284 μl, 1.9 mmol) in THF (1 ml) is added onto a solution of (3-bromo-propyl)-carbamic acid tert-butyl ester (407 mg, 1.71 mmol) in THF (1 ml). The resulting solution is stirred at rt for 2 h. It becomes slowly turbid and the undesired solid is filtered on a fritted funnel. The solution is diluted with THF (2 ml) and DIPEA (491 mg, 650 μl, 3.8 mmol) is added. The mixture is poured onto a suspension of 2-chlorotrityl chloride resin (200-400 mesh), 1% DVB (1.0-1.6 mmol/g, 475 mg, 0.76 mmol) in THF (1 ml) and allowed to stir for 3 h. The resin is filtered and rinsed with THF. The solvent is removed in vacuo and the residue diluted with dichloromethane (5 ml). This organic phase is washed with an aqueous citric acid solution (pH=4) and with water. The solvent is evaporated under reduced pressure. The same purification process is repeated using dichloromethane instead of THF as the solvent. The obtained organic phase is washed with a saturated aqueous KH2PO4 solution and water. Evaporation of the solvent in vacuo affords a residue that is purified by flash chromatography on silica-gel (AcOEt/heptane, 1:2), yielding the title compound (587 mg) in 73% as a colourless oil: tR=2.41 min (LC-2), ESI-MS (pos.): m/z 422.50 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.37 (s, 9H, tBu), 1.39 (s, 9H, tBu), 1.74 (quint. 2H, CH2CH2N), 3.20 (dd, 2H), 3.38 (t, 2H), 4.67 (s, 2H, CH2CO2), 5.82 (br. s, 1H, NH), 7.10-7.29 (m, 3Harom), 7.65 (m, 1Harom).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH:15]=1)(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][C:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:6]([NH2:5])(=[O:8])=[O:7])=[CH:15]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccsc1C1=CC(=O)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccsc1C1=CC(=O)CCC1
Yield: 58.1 %

Procedure:
A solution of the product from Example 1 (6.0 g, 0.0192 mole) in trifluoroacetic acid (20 mL) was stirred at room temperature overnight, was stripped to an oil, and crystallized with ethyl acetate/ether to yield 2.87 g solid, m.p. 140°-147° C.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1)[NH2:2].[C:13](OCC)(OCC)(OCC)[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[N:7]2[C:3]([S:4][C:5]3[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:6]=32)=[N:1][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1cccc2sc(NN)nc12
Solvent: Cc1ccccc1C
Product: Cc1cccc2sc3nnc(C)n3c12
Temperature: 25 °C

Procedure:
A solution of 6.1 grams of 2-hydrazino-4-methylbenzothiazole (0.034 mole) and 6.4 grams of triethyl orthoacetate (0.04 mole) in 200 milliliters of xylene was brought to reflux temperature over a period of 5 hours and thereafter refluxed for 96 hours. The reaction mixture was then concentrated to one-fourth of the original volume and allowed to cool to room temperature. The 3,5-dimethyl-s-triazolo(3,4-b)benzothiazole product was separated by filtration, 4 grams, m.p., 196°-8° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[NH2:15][C:13]1[S:14][CH:2]=[C:3]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: NC(N)=S
Reactant: O=C(CCl)Cc1ccccc1
Solvent: CCO
Product: Nc1nc(Cc2ccccc2)cs1
Yield: 30.1 %

Procedure:
5.0 g of benzyl chloromethyl ketone (Example 211a) was dissolved in 20 ml of ethanol and 2.3 g of thiourea was added thereto, followed by heating under reflux for 3 hours. After cooling as it was, the solvent was removed and the residue was subjected to NH-silica gel column chromatography using 50% ethyl acetate/hexane and ethyl acetate as an eluent for separation and purification, to give 1.7 g of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Yield: 28.7 %

Procedure:
2,6-Diacetylpyridine (7.3 g, 44.8 mmol) and 2,4,6-trimethylaniline (5.74 g, 42.55 mmol) were dissolved in 450 ml of toluene. To this solution, 4 Å molecular sieves and a small amount of p-toluenesulphonic acid (0.22 mmol) were added. The mixture was refluxed for 16 hours. After filtration the solvent was removed in vacuo. Several crystallisations from ethanol yielded 3.42 g (28.7%) of monoimine (1). 1H-NMR (CDCl3) δ 8.55 (d, 1H, Py-Hm), 8.11(d, 1H, Py-Hm), 7.92 (t, 1H, Py-Hp) 6.89 (s, 2H, ArH), 2.77(s, 3H, Me), 2.27 (s, 3H, Me), 2.22 (s, 3H, Me), 1.99 (s, 6H, Me).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][C:11](OCC)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+]>C(O)C>[OH:12][CH2:11][CH2:10][O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: CCOC(=O)COc1cccc(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc(OCCO)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
A suspension of ethyl [(3-cyanophenyl)oxy]acetate obtained in Reference Example 29 (8.00 g, 39.0 mmol) and sodium borohydride (1.47 g, 39.0 mmol) in ethanol (120 mL) was stirred at 50° C. for 15 hr, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a white powder (5.85 g, 92%).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Br[C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)C(C)(C)Br
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.7 %

Procedure:
To a solution of 4-(adamantan-1-yl)phenol (0.8 g, 3.50 mmol) in N,N-dimethylformamide (8 mL) was added anhydrous potassium carbonate (1.45 g, 10.51 mmol) and methyl 2-bromo-2-methylpropanoate (1.15 g, 7.0 mmol), and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give methyl 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoate as colorless oil (1.1 g, 94.1% yield).