Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(=O)OC(C)(C)C)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)s1
Yield: 70.3 %

Procedure:
0.846 g (3 mmol) of the product obtained in step d) were dissolved in 100 ml of dry ethanol. 150 mg of 10% palladium on charcoal were added, and the suspension was hydrogenated at 50° C. and 4 bar hydrogen pressure. After filtration the solvent was removed in vacuo. 0.6 g of a colourless oil were obtained.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11]([F:16])=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1)=O>CO.C(N(CC)CC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][OH:3])[C:10]=2[C:11]=1[F:16]
Reactant: O=COCCn1cnc2ccc(Cl)c(F)c21
Solvent: CCN(CC)CC
Solvent: CO
Product: OCCn1cnc2ccc(Cl)c(F)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
2-(6-Chloro-7-fluoro-1H-benzimidazol-1-yl)ethyl formate (1.1 g, 4.53 mmol) is dissolved in MeOH (50.0 mL) with triethylamine (5.0 mL) and stirred at room temperature 18 hours. The reaction mixture is then concentrated to provide the expected product 2-(6-chloro-7-fluoro-1H-benzimidazol-1-yl)ethanol (0.95 g, 98%) as a white powder. 1H NMR (400 MHz, METHANOL-D4) δ ppm 3.90 (t, J=4.69 Hz, 2H) 4.47 (t, J=5.08 Hz, 2H) 7.30 (dd, J=8.79, 6.84 Hz, 1H) 7.45 (dd, J=8.59, 0.78 Hz, 1H) 8.16-8.19 (m, 1H)
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CN(C)C=O.[Br:12][C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([OH:17])=O>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([C:13]1[CH:21]=[CH:20][C:19]([CH2:1][CH3:2])=[CH:18][CH:14]=1)=[O:17]
Reactant: O=C(O)c1cc(I)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(I)ccc2Br)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Oxalyl chloride (9 mL) and dimethylformamide (0.5 mL) are added to a mixture of 2-bromo-5-iodo-benzoic acid (25 g) in dichloromethane (80 ml). The reaction mixture is stirred for 14 h at room temperature, then filtered and separated from all volatile constituents in a rotary evaporator. The residue is dissolved in dichloromethane (50 mL) and ethyl-benzene (23 mL) and the resultant solution is cooled to −5° C. Then aluminum trichloride (12.5 g) is added batchwise so that the temperature maintains below 10° C. The solution is warmed slowly to room temperature and stirred overnight. The solution is poured onto crushed ice, the organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with hydrochloric acid (1 mol/l), sodium hydroxide solution (1 mol/l) and with brine. The organic phase is dried over sodium sulphate and the solvent is removed to give the product as an oil that crystallizes on standing.
Reaction SMILES: [CH2:1]([CH:3]=[C:4]([CH3:15])[C:5]([O:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:16]([OH:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].[C:22]([O:27][CH3:28])(=[O:26])[C:23]([CH3:25])=[CH2:24]>C(C(C)=O)C.N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=O>[CH2:1]([CH:3]=[C:4]([CH3:15])[C:5]([O:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH3:2].[CH3:28][O:27][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC
Agent: CCC=C(C)C(=O)OOc1ccccc1
Agent: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Solvent: CCC(C)=O
Product: C=C(C)C(=O)[O-]
Temperature: 72 °C

Procedure:
(Synthesis of Water-Insoluble Polymer Dispersant P-1) 88 g of methyl ethyl ketone was added to a 1000 ml three-necked flask equipped with an agitator and a condenser, and was heated to 72° C. under a nitrogen atmosphere. To this, a solution of 0.85 g of dimethyl 2,2′-azobisisobutyrate, 50 g of phenoxy ethylmethacrylate, 13 g of methacrylic acid and 37 g of methyl methacrylate dissolved in 50 g of methyl ethyl ketone was added dropwise over 3 hours. Once the dropwise addition was completed, the mixture was reacted for one more hour, and then a solution of 0.42 g of dimethyl 2,2′-azobisisobutyrate dissolved in 2 g of methyl ethyl ketone was added. The temperature was raised to 78° C., and the mixture was heated for 4 hours. The obtained reaction solution was precipitated two times in large excess of hexane, and the precipitated resin was dried to obtain 96.5 g of phenoxy ethylmethacrylate/methylmethacrylate/methacrylate (copolymerization ratio [% by mass ratio]=50/37/13) copolymer (resin dispersant P-1).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=O)[CH:38]=[C:39]([F:41])[CH:40]=1>CS(O)(=O)=O>[F:41][C:39]1[CH:38]=[C:37]2[C:36](=[C:35]([F:34])[CH:40]=1)[C:45](=[O:47])[CH2:44][CH2:43][CH2:42]2
Reactant: O=C(O)CCCc1cc(F)cc(F)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1CCCc2cc(F)cc(F)c21
Temperature: 65 °C

Procedure:
This step follows the general procedure reported by Eaton et al., Organic Chemistry 38(23): 4071-4073 (1973). Eaton's reagent, prepared from 32 g phosphorus pentoxide and 192 mL methanesulfonic acid, was heated at 65° C. A solution of 4-(3,5-difluoro-phenyl)-butyric acid (12.85 grams, 64.19 mmoles, prepared as described by Repke et al., U.S. Pat. No. 5,538,988) in 30 mL methanesulfonic acid was added and the reaction mixture was heated at 65° C. for 35 minutes. The mixture was poured onto 1 L cracked ice and the product was extracted twice with 500 mL of a mixture of 2 parts diethyl ether to 1 part ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, water, saturated sodium chloride and then it was dried (magnesium sulfate). The solution was concentrated under reduced pressure. 6,8-Difluoro-3,4-dihydro-2H-naphthalen-1-one was isolated by recrystallization from hexane, 9.55 grams (82%), m.p. 57-58° C.
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:19](=[CH:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[CH:2].CC(C)([O-])C.[K+].[Al]>>[C:1]([C@@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:19](=[CH:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[CH:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: CC(C)(C)[O-]
Agent: [Al]
Agent: [K+]
Product: C#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 48 h

Procedure:
17α-Ethynyl-17β-hydroxyandrosta-4,9(11)-dien-3-one (III A, (.S. Pat. No. 3,441,559, 0.3 g) and potassium t-butoxide (0.119 g) are combined in a vial which is then sealed with a septum and aluminum cap. The vial air-space is evacuated under reduced pressure, ethylene diamine (5 ml) is then added by a syringe followed by acetylene gas purge into the vapor space. The mixture is stirred at 20°-25° for 48 hours at which time TLC (ethyl acetate/hexane:50/50) indicates the title compound is obtained.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[CH:15][C:10]3=[C:9]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[C:9]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCc1nc(C2CCCCC2)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCc1nc(C2CCCCC2)n2c1cnc1[nH]ccc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To solution of ethyl 3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoate (0.031 g, 0.063 mmol, prepared using W from Example #12 Step A) in 1,4-dioxane (3 mL) was added NaOH (2 N aqueous, 1.57 mL, 3.13 mmol). The reaction mixture was heated to about 65° C. After about 2 h, the reaction mixture was cooled to ambient temperature and the pH of the mixture was adjusted to about 1 with 1 N aqueous HCl. The reaction mixture was concd in vacuo and purified by chromatography on silica gel (12 g) eluting with 2-10% MeOH in DCM to provide 3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)propanoic acid (0.005 g, 26%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.68 min; MS m/z: 313 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16](O)=[O:17])=[C:9]3[N:8]=2)[CH:4]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[OH:26])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C@H:52]([OH:55])[CH2:53][Cl:54].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:54][CH2:53][C@@H:52]([OH:55])[CH2:51][NH:50][C:16]([C:15]1[CH:14]=[N:13][N:10]2[CH:11]=[CH:12][C:7]([N:5]3[CH2:6][C:2]([F:1])([F:27])[CH2:3][CH:4]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[OH:26])=[N:8][C:9]=12)=[O:17]
Reactant: O=C(O)c1cnn2ccc(N3CC(F)(F)CC3c3cc(F)ccc3O)nc12
Reactant: NC[C@H](O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NC[C@H](O)CCl)c1cnn2ccc(N3CC(F)(F)CC3c3cc(F)ccc3O)nc12
Reaction time: 1 h
Yield: 104.7 %

Procedure:
To a mixture of 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.047 g, 0.124 mmol) and HOBT (0.0252 g, 0.186 mmol) in DMF (1 mL) at ambient temperature was added EDCI (0.0357 g, 0.186 mmol). The resulting mixture was stirred for 1 hour. To this mixture was added (S)-1-amino-3-chloropropan-2-ol hydrochloride (Example 19, Step A; 0.0218 g, 0.149 mmol) followed by DIEA (0.0656 mL, 0.373 mmol) at ambient temperature. The resulting mixture was stirred for 48 hours. The reaction mixture was diluted with EtOAc (10 mL), and the organic layer was washed with a 1:1 mixture of brine and water. The aqueous layer was separated and extracted with EtOAc (2×10 mL). The combined organic layers were washed with a 1:1 mixture of brine and water (15 mL) and combined with the organic layer obtained previously. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford N-((S)-3-chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.061 g, 105% yield). LC/MS (ES+APCI) m/z=468.1 (M−H).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COc1ccc(C=Cc2cccc[n+]2[O-])cc1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and p-anisaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=227 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])[CH:11]=[CH:10][C:9]=1[NH:28]C(OC(C)(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[C:24]([NH:23][S:20]([C:15]1[C:14]([C:12]2[CH:11]=[CH:10][C:9]([NH2:28])=[C:8]([NH2:7])[CH:13]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:22])=[O:21])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(N)c1
Yield: 185.4 %

Procedure:
2-tert-butoxycarbonylamino-5-(2-tert-butylaminosulfonyl-phenyl)-phenyl carbamic acid tert-butyl ester (5.4 g, 10.3 mmol) in a solution of 4M HCl in 1,4-dioxane (250 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed with saturated sodium bicarbonate and water (pH=7). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc: hexanes, 1:1) to afford the title compound as a brown viscous oil (6.1 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.12 (dd, 1H, J=7.9, J=1.7), 7.51 (td, 1H, J=7.5 Hz, J=1.5 Hz), 7.42 (td, 1H, J=7.6 Hz, J=1.3 Hz), 7.30 (dd, 1H, J=7.8, J=1.5), 6.94 (d, 1H, J=1.9), 6.80 (m, 2H), 3.80 (s, NH), 3.50 (br s, 4H), 0.98 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C16H21N3O2S: 320.42 (M+H), Found 320.9.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.C(O)C.O>[Cl:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:47]([CH3:60])=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(Cl)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(Cl)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 31.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.3 mmol) was coupled with 1-(3-chlorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 54) (107 mg, 0.33 mmol) in sodium carbonate (99 mg, 0.9 mmol), Pd(dppf)Cl2 (12 mg, 0.01 mmol), toluene/ethanol/water (2/2/1 ml) to give 70 mg (31% yield) of titled compound.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2c3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A mixture of 10.00 g of acridan (55.2 mmol), 0.26 g of Pd(OAc)2 (0.11 mmol), 0.20 g of tri-t-butylphosphine (0.88 mmol), 7.96 g of sodium t-butoxide (82.8 mmol), and 12.39 g of 1-bromo-4-nitrobenzene (61.3 mmol) in 150 mL of dry toluene (MgSO4) was stirred at room temperature under inert atmosphere for 18 h. The reaction mixture was extracted with 1 L of CH2Cl2 and filtered through silica gel. The filtrate chromatographed on silica gel with 2.5-5% ethyl acetate in hexanes to afford white solid that was triturated in hexanes, filtered and dried to yield 4.00 g (24%) of pure N-(4-nitrophenyl)acridan.
Reaction SMILES: [CH2:1]1[O:30][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][N:10]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[C:9](=[O:28])[CH2:8][C:7]=3[CH:29]=[C:3]2[O:2]1.O.NN>C(O)C.Cl.[Ni]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:10]2[C:9](=[O:28])[CH2:8][C:7]3[CH:29]=[C:3]4[O:2][CH2:1][O:30][C:4]4=[CH:5][C:6]=3[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11]2)=[CH:20][CH:21]=1
Reactant: O=C1Cc2cc3c(cc2C(c2ccccc2)=NN1c1ccc([N+](=O)[O-])cc1)OCO3
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2N=C(c3ccccc3)c3cc4c(cc3CC2=O)OCO4)cc1
Reaction time: 0.67 h
Yield: 65.5 %

Procedure:
To a solution of 7,8-methylenedioxy-3-(4-nitrophenyl)-1-phenyl-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (15 mg, 0.037 mmol) in ethanol (5 mL) was added HCl (conc. 2 drops), hydrazine hydrate (0.3 mL) and Raney Ni (excess) and the reaction was stirred for 40 min. The excess Raney Ni was removed by filtration and the pure product (9 mg, 66%) was obtained by flash chromatography (12.5% acetone in CH2Cl2). 1H NMR (CDCl3) 7.60 (m, 2H), 7.42 (m, 3H), 7.20 (d, J=8.6, 2H), 6.92 (s, 1H), 6.71 (d, J=8.6, 2H), 6.68 (s, 1H), 6.07 (s, 1H), 6.03 (s, 1H), 3.80-3.45 (m, 4H).
Reaction SMILES: Cl.C([Si](C)(C)[O:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([Cl:24])=[C:18]([Cl:23])[CH:19]=3)[C:14]2=[O:25])[CH2:9]1)(C)(C)C>CO>[Cl:24][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][C:18]=1[Cl:23])[C@H:21]([OH:22])[N:13]([CH:10]1[CH2:11][CH2:12][CH:8]([OH:7])[CH2:9]1)[C@@H:14]2[OH:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1
Agent: Cl
Solvent: CO
Product: OC1CCC(N2[C@H](O)c3cc(Cl)c(Cl)cc3[C@@H]2O)C1
Yield: 94 %

Procedure:
To a flask containing HCl (37%, 5 mL) and methanol (155 mL) was added cis 2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-5,6-dichloro-isoindole-1,3-dione (1.7 g, 4.1 mmol). The mixture was placed in an ultrasound bath until all of the solid had dissolved (15 minutes) then evaporated to give cis 5,6-dichloro-2-(3-hydroxy-cyclopentyl)-2,3-dihydro-1H-isoindole-1,3-diol (1.172 g, 95% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27])#[N:20].[CH2:28]1[O:30][CH2:29]1>C1COCC1>[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH2:28][CH2:29][OH:30])#[N:20]
Reactant: Cc1ccncc1C#N
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1cnccc1CCCO
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Diisopropylamine (2.5 g, 25 mmol) is dissolved in THF (30 ml), and thereto is added a solution of n-butyl lithium in hexane (14.3 ml, 24 mmol) at −70° C. The mixture is stirred for 15 minutes, and thereto is added a solution of 3-cyano-4-methylpyridine (2.4 g, 20 mmol) obtained in Reference Example 33 in THF (20 ml). Ten minutes thereafter, ethylene oxide (1.1 g, 24 mmol) is added to the mixture, and the mixture is warmed to 20° C. over a period of time for one hour. The reaction is quenched with a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (150 ml×2). The organic layer is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (1.2 g) as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.O.[H][H]>CO.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][NH2:14])([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CC(C)(NC(=O)CCNC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(NC(=O)CCN)c1ccccc1
Yield: 84.2 %

Procedure:
1.5 g of palladium-on-carbon were suspended in a solution of 4.51 g of N-(α,α-dimethylbenzyl)-3-(benzyloxycarbonylamino)propionamide (prepared as described in Preparation 2) in 110 ml of an 8:2:1 by volume mixture in methanol, acetic acid and water, and then hydrogen was passed through the solution for 4 hours at room temperature under normal atmospheric pressure. Undissolved materials were filtered off, the pH was adjusted to a value of 10 by the addition of a 10% w/v aqueous solution of sodium hydroxide, and then the mixture was extracted with 150 ml of ethyl acetate. The solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure to give 2.3 g of the title compound as an oil.
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].C(O)(=O)C(C(C(O)=O)O)O>>[C:8]([OH:10])(=[O:9])[C@H:6]([C@@H:4]([C:1]([OH:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C(O)C(O)C(O)C(=O)O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O

Procedure:
The tartrate is obtained conducting the hydrogenolysis of the Z benzyloxycarbonyl group in the presence of tartaric acid. The L acid and the D-tartaric acid both provide a comparable salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:21]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[CH2:26][CH2:25]1)(=[O:23])[CH3:22]>O1CCCC1.C(OCC)(=O)C.O.[Cl-].[NH4+]>[Br:1][C:2]1[N:3]=[C:4]([C:8]2[S:12][C:11]([C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[CH2:26][CH2:25]3)([OH:23])[CH3:22])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Reactant: Brc1cccc(-c2cncs2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(-c3cccc(Br)n3)s2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-6-(1,3-thiazol-5-yl)pyridine (457 mg, 1.895 mmol) in tetrahydrofuran (20 mL) at −78° C. was added lithium diisopropyl amide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 1.106 mmol, 1.990 mmol) over three minutes. After 30 minutes, a solution of butyl trans-4-acetylcyclohexanecarboxylate (450 mg, 1.990 mmol) in tetrahydrofuran (3 mL) was added to the reaction mixture. After an additional 70 minutes, a saturated aqueous ammonium chloride solution (10 mL) was added. Then, the reaction mixture was allowed to warm to room temperature before being diluted with ethyl acetate (50 mL), water (2 mL), and saturated aqueous ammonium chloride solution (10 mL). The layers were separated and the organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-20% ethyl acetate/dichloromethane) to give butyl trans-4-{1-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cyclohexanecarboxylate. MS ESI calc'd. for C21H27BrN2O3S [M+H]+ 467 and 469. found 467 and 469. Two enantiomers were separated by chiral super critical fluid chromatography (Chiral Technology IC-H, 2.1×25 cm, 5 uM, 70/30 ethanol/CO2, Flow Rate: 70 mL/min, 6 min run time, WL: 220 nm) Elution was observed at 3.98 min and 4.76 min. Pooled fractions of each peak were concentrated under reduced pressure.