Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][O:14]2)[CH:4]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][O:14]2)[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)c(OCC2CCOCO2)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(CO)c(OCC2CCOCO2)c1

Procedure:
Using a Parr hydrogenator, 3.4 grams (0.014 mole) of 4-ethyl-2-(1,3-dioxan-4-ylmethoxy)benzaldehyde in 200 mL of ethanol was hydrogenated in the presence of 5% palladium on carbon for two hours at 50 psi. The yield of subject compound was 2.3 grams, following purification by column chromatography on silica gel. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[C:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[C:3]1=[O:24].[H][H]>C(O)(=O)C>[NH:14]1[CH2:15][CH2:16][CH:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:24])[CH2:12][CH2:13]1
Reactant: CN1C(=O)C(=C2CCN(Cc3ccccc3)CC2)c2ccccc21
Reactant: [H][H]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C1C1CCNCC1
Yield: 87.4 %

Procedure:
A mixture of 16 g of the product of Step A, 150 ml of acetic acid and 2 g of 10% palladized carbon was saturated with hydrogen at 50° C. for 2 hours and after the reaction was finished, the mixture was filtered. The filtrate was evaporated to dryness and the residue was taken up in water. The mixture was made alkaline with concentrated sodium hydroxide solution and was extracted 4 times with 100 ml of methylene chloride. The combined organic phases were washed with a little water, dried and evaporated to dryness to obtain 9.5 g of 1,3-dihydro-3-(piperidin-4-yl)-2H-indol-2-one melting at ≃80° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:13]([C:11]1[S:12][C:8]([CH3:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14])([CH3:6])[CH3:5]
Reactant: Cc1sc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(N)CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (1.11 g, 12.4 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) 5-methyl-4-nitrothiophene-2-sulfonyl chloride [CAS No. 61714-77-0] and triethylamine (0.63 ml, 4.56 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/MeOH) and subsequent crystallization (ethyl acetate/heptane) to yield 5-methyl-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.71 g, 58%) as a light brown solid. MS (ISP) 293.0 [(M−H)−]; mp 126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]1=[O:12].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:11][C:8]1[CH:9]=[CH:10][N:5]([CH2:4][C:3]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=2[Cl:1])[C:6](=[O:12])[CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1cc(O)ccn1Cc1ccc(Cl)cc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ccn1Cc1ccc(Cl)cc1Cl

Procedure:
1-(2,4-dichloro-benzyl)-4-hydroxy-1H-pyridin-2-one synthesized in Example 14 was dissolved in DMF followed by adding NaH and benzyl bromide to obtain 4-benzyloxy-1-(2,4-dichloro-benzyl)-1H-pyridin-2-one and the titled compound in the ratio of 1:1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:30]=1>>[CH2:39]([O:38][C:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)=[O:37])[CH3:40]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and ethyl 4-aminophenylacetate
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]1[CH2:18][CH2:17][C:16]2[C:19]([CH3:28])=[CH:20][CH:21]=[C:22]([NH:23][NH:24][C:25]([OH:27])=[O:26])[C:15]=2[O:14]1>C(Cl)Cl>[CH3:1][O:26][C:25]([N:24]=[N:23][C:22]1[C:15]2[O:14][CH:13]([CH3:12])[CH2:18][CH2:17][C:16]=2[C:19]([CH3:28])=[CH:20][CH:21]=1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(NNC(=O)O)c2c1CCC(C)O2
Solvent: ClCCl
Product: COC(=O)N=Nc1ccc(C)c2c1OC(C)CC2
Temperature: 35 °C

Procedure:
A solution of 13.8 g of MCPBA in 100 ml of methylene chloride was added drop-by-drop over 10 minutes to a stirred solution of 16.1 g of 1G in 150 ml of methylene chloride at room temperature. The resulting mixture was stirred and refluxed (35° C.) for 30 minutes, then washed with 10% aqueous sodium carbonate solution. The resulting methylene chloride solution was dried (MgSO4), and the solvent was evaporated. The residue was purified by column chromatography over silica gel, using a 1:4:20 v:v:v mixture of THF, ethyl acetate and hexane as eluent, to give 1, as a brick red solid, m.p.: 95°-97° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH3:32]>C(Cl)Cl>[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH3:32])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CNCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N-(2-methoxyethyl)methylamine (0.80 ml; 7.42 mmol; 5.00 eq) are added. After 45 minutes at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (21) as a beige solid (478 mg; 83%).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14]>CN(C=O)C>[CH2:11]([O:12][C:13](=[O:15])[CH2:14][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:10]
Reactant: Oc1cccnc1
Reactant: CC(=O)OCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-hydroxypyridine sodium salt, 6.4 g (36.0 mmol) in 200 mL of DMF was added 3.3 mL (30.0 mmol) of bromoethylacetate. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using MeOH/chloroform as eluent and concentrated to dryness to give 3.8 g (70%) of the desired product as a tan oil. MS (ion spray) 182.1 (M+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:62])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[O:62])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)N(C)C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)N(C)C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy) phenyl]-N-[4-[[[1-[4-(dimethylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (400 mg) in dichloromethane (30 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.2 g) in dichloromethane (15 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica get, ethyl acetate→ethanol:ethyl acetate 1:49), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-[4-(dimethylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 421) (377 mg) as yellow amorphous.
Reaction SMILES: C1COCC1.[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[C:8]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=2)[CH:7]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>CCN(CC)CC>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:8]3[CH:7]=[N:6][N:10]4[CH:11]=[CH:12][CH:13]=[N:14][C:9]=34)[CH:20]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccnc(-c2cnn3cccnc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(-c2cnn3cccnc23)c1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a THF suspension of 2-(pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-4-amine (8g) was added Et3N and 4-fluorobenzoyl chloride. The reaction mixture was stirred at 50° C. for 2 hours until LS/MS indicated the desired product was the major peak. After aqueous work up, the residue was dissolved in 1 ml of DMSO and purified by preparative HPLC. The product was obtained as a solid (10 mg).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].CN(C)C=O>O>[C:17]([O:20][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: CC(Br)c1ccc2occ(C#N)c(=O)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 70 °C
Reaction time: 0.83 h

Procedure:
A mixture of 5.56 parts of 6-(1-bromoethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile, 1.640 parts of anhydrous sodium acetate and 8 parts by volume of dimethylformamide is heated at 70° C under stirring for 50 minutes. After cooling, the reaction mixture is poured into 100 parts by volume of water to give precipitates, which are collected and recrystallized from ethanol and subsequently ethyl acetate. The procedure yields 2.90 parts of 6-(1-acetoxy-ethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile. Melting point: 148°-149° C
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[CH3:11][NH:12][NH2:13]>O>[NH2:8][C:7]1[C:6]([C:9]#[N:10])=[C:3]([S:4][CH3:5])[N:12]([CH3:11])[N:13]=1
Reactant: CNN
Reactant: CSC(SC)=C(C#N)C#N
Solvent: O
Product: CSc1c(C#N)c(N)nn1C
Reaction time: 1 h

Procedure:
9.63 g (56.6 mmol) [Bis(methylmercapto)methylene]-malononitrile was suspended in 50 ml water and treated with 3.7 ml (67.9 mmol) methylhydrazine. The mixture was heated at boiling for 1 hour, the reaction solution cooled, the precipitate suction filtered and recrystallised from ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:25])[CH:3]=1.C(N(CC)CC)C>CCO.[Pd]>[O:25]=[C:9]1[N:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]1[C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2cc(Cl)ncn2)c2ccccc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccncn2)c2ccccc21
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [3-(6-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (260 mg, 0.720 mmol), 10% Pd/C (23 mg) and triethylamine (0.150 mL, 1.08 mmol) in EtOH (5 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 2 h. The mixture was filtered through a pad of Celite, washing with EtOH, and the filtrate was concentrated to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH2:28][CH3:29])=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH2:28][CH3:29])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(CC)o3)cc2)nc1Cl
Yield: 8.7 %

Procedure:
The same operation as in Example (91d) was performed using ethyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (99c) (0.12 g, 2.88 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (2 mL) and tetrahydrofuran (5 mL), to obtain 97 mg of the title compound as a light pink solid (87%).
Reaction SMILES: C([Li])CCC.[CH:6]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)[CH2:8][CH2:7]1.[B:18](OC)([O:21]C)[O:19]C>O1CCCC1>[CH:6]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([B:18]([OH:21])[OH:19])=[CH:13][CH:12]=2)[CH2:8][CH2:7]1
Reactant: Ic1ccc(OCC2CC2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Butyl lithium (2.5 M in hexane, 14.4 mL, 36 mmol) was added dropwise (5 min) to a cooled (−78° C.) and stirred solution of 4-(cyclopropylmethoxy)iodobenzene 1 (9.00 g, 32.8 mmol) in tetrahydrofuran (100 mL). After 20 min, trimethyl borate (11.3 mL, 10.4 g, 100 mmol) was added dropwise (10 mL). The reaction was stirred for an additional 20 min, and was then allowed to warm to rt. The reaction was quenched with 1 M hydrochloric acid (300 mL) and stirring was continued for 30 min. The product was extracted with diethyl ether (4×100 mL) and then the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in toluene and then concentrated. This operation was repeated (5×) until the distillate was colorless and left 5.67 g (90%) of crude product. This material was used without purification or analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C@H:5]1[CH2:9][CH2:8][C@@H:7](O)[CH2:6]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][C@H:7]1[CH2:8][CH2:9][C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:11])[CH2:6]1
Reactant: COC(=O)C[C@H]1CC[C@@H](O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](Br)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To (1S,3R)-(3-hydroxy-cyclopentyl)acetic acid methyl ester (2.0 g, 12.6 mmol) in 10 mL of DCM at 0° C. was added PPh3 (3.49 g, 13.3 mmol, 1.05 eq.), followed by CBr4 (4.41 g, 13.3 mmol, 1.05 eq.) slowly. The mixture was stirred at room temperature overnight. The reaction mixture was filtered through a thin layer silica gel and the filtrate was concentrated down. The residue was purified by silica gel chromatography with (15% EtOAc in hexanes) to provide 1.96 g of methyl 2-((1R,3S)-3-bromocyclopentyl)acetate 101.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1>C(O)C.CO>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCCC3c3ccccc3)CCO4)cc2[nH]1
Solvent: CO
Solvent: CCO
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCC[C@@H]3c3ccccc3)CCO4)cc2[nH]1

Procedure:
Prepared by chiral preparative HPLC separation of racemic 7-(2-methyl-1H-benzimidazol-6-yl)-4-[(2-phenylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 18.0 mL/min and detection at 220 nm. The isomer with retention time 11.20 min. was assigned as the (R)-enantiomer. Chiral analytical HPLC was carried out using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 0.7 mL/min with detection at 254/220 nm. This isomer gave a retention time 9.51 min and ee>99%. MS (EI) C29H30N4O2: 467 (MH+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cn2)cn1

Procedure:
By carrying out the operation analogously to example 213, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-methoxy-5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:24]([O-])([OH:26])=[O:25]>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)ccc3O2)cc1
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3cc(F)c([N+](=O)[O-])cc3O2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 19.0 g (56.2 mmole) of {(2R)-6-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate in 200 mL of 1,2-dichloro-ethane in an ice/water bath was added dropwise a solution of 8.35 mL (0.197 mole) of fuming nitric acid (d 1.49) and the mixture was stirred for 2 hours at 0° C. After the reaction was complete, it was quenched with ice and diluted with 500 mL of methylene chloride. After the ice had melted, the organic layer was separated and washed with equal volumes of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to a crude yellow solid. This was column chromatographed on silica gel with 1:1 hexane/methylene chloride as eluant to give 18.6 g of the (R)-enantiomer of the title compound as a light yellow solid (m.p. 106-107° C.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:42](N)[CH2:43]CC.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([NH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:29]=[N:30]1)[CH2:37][CH2:42][CH3:43]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: CCCCN
Solvent: NCCO
Solvent: O=C(O)C(F)(F)F
Product: CCCCNCCn1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Yield: 26 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 1-butanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 7 mg of the title compound (26%).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(N(C(C)C)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][NH2:2])=[O:16])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
) A solution of hydrazine (0.023 mol) and N,N-dimethyl-4-pyridinamine (catalytic quantity) in CH2Cl2 (50 ml) was cooled in an ice-water bath. Half of a solution of 4-benzoylbenzoyl chloride (0.023 mol) in CH2Cl2(60 ml) was added dropwise. The other half of this solution, and a solution of N,N-bis(1-methylethyl)ethanamine (0.023 mol) in CH2Cl2 (40 ml) were added simultaneously and dropwise. The resulting reaction mixture was stirred for 5 hours at RT. The crude reaction mixture was filtered and the filtrate was washed with water and extracted. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 1.9 g (34%) of 4-benzoylbenzoic acid hydrazide (interm. 12)