Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>[Pt]=O.C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:21]3[C:22]4[C:17]([CH2:18][CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CCC(C(=O)Nc2cccc3cccnc23)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(=O)N1CCC(c2nc3cccc4c3n2CCC4)CC1
Yield: 102.7 %

Procedure:
A mixture of 1-acetyl-N-(quinolin-8-yl)-4-piperidinecarboxamide (51.28 g), glacial acetic acid (800 ml), and platinum oxide (4.00 g) was shaken under hydrogen at ambient temperature until the calculated amount of hydrogen was consumed. The platinum oxide was filtered through a bed of celite and the filter cake was washed with acetic acid. The filtrate was evaporated to ~200 ml, and was then stirred under reflux for four hrs, basified with 10% ammonium hydroxide solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was combined with material from another reaction mixture. The combined residue was purified by high performance liquid chromatography (silica gel; 20:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was crystallized from ethyl acetate and then recrystallized from ethyl acetate to give 50.2 g (76%) of product, mp 139°-140° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:16]([CH3:17])=[C:15](/[CH:18]=[C:19]3\[C:20](=[O:40])[NH:21][C:22]4[C:27]\3=[CH:26][C:25]([S:28]([CH2:31][C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[NH:14][C:13]=2[CH3:41])=[O:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:42]([NH:49][C@@H:50]([C:52]([OH:54])=O)[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].[C:55](P(=O)(OCC)OCC)#N>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[NH:49][C:50]([CH3:51])([CH3:55])[C:52]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:16]([CH3:17])=[C:15](/[CH:18]=[C:19]3\[C:20](=[O:40])[NH:21][C:22]4[C:27]\3=[CH:26][C:25]([S:28]([CH2:31][C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[NH:14][C:13]=2[CH3:41])=[O:11])[CH2:2][CH2:3]1)=[O:54])([CH3:46])([CH3:47])[CH3:48]
Reactant: CCOP(=O)(C#N)OCC
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCNCC1
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-piperazin-1-yl-ethyl)-amide (150 mg, 0.24 mmol) and N-Boc D-alanine (19 mg, 1 eq.) in DCM (5 mL) cooled in an ice bath was added diethyl cyanophosphonate (48 mg, 1.2 eq.) in DCM (0.5 mL) followed by a dropwise addition of TEA (0.04 mL, 1 eq.) in DCM (0.5 mL). The mixture was then stirred at rt for overnight. The reaction was diluted with DCM, washed with 10% potassium carbonate, water, dried and concentrated to give (2-{4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester as a red wax.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[F:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: OB(O)c1ccccc1F
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(-c2ccccc2F)c1F
Temperature: 100 °C

Procedure:
To a solution of 1-bromo-2-fluoro-3-nitrobenzene [58534-94-4] (150 mg, 0.68 mmol) and 2-fluorophenylboronic acid [1193-03-9] (191 mg, 1.36 mmol) in dioxane (4 mL) and water (1 mL) was added potassium carbonate (236 mg, 1.70 mmol) and Pd(dppf)Cl2CH2Cl2 adduct (55.7 mg, 0.068 mmol). The solution was heated for 30 min at 100° C. under microwave irradiation. The reaction mixture was diluted with CH2Cl2 and the resulting solution was washed successively with saturated aqueous NaHCO3 solution, 1N HCl solution and brine, then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the purified fractions the title compound. MS (LC-MS): 236 [M+H]+; tR (HPLC conditions k): 3.81 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([NH:15][C:16](=O)[CH3:17])[C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:16]([NH:15][CH:3]([C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH:2]([CH3:19])[CH3:1])[CH3:17]
Reactant: CC(=O)NC(c1nc(-c2ccccc2)c[nH]1)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNC(c1nc(-c2ccccc2)c[nH]1)C(C)C
Temperature: 25 °C

Procedure:
A solution of N-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-acetamide (0.077 g, 0.30 mmol) in THF (2.0 mL) was added dropwise over 10 min to a refluxing 1.0 M solution of LiAlH4 in THF (3.0 mL). The reaction was maintained at reflux for 11 h, cooled to rt, and quenched by sequential treatment with 0.11 mL of cold water (5° C.), 0.11 mL of 15% NaOH in aqueous solution, and 0.33 mL of cold water (5° C.). The resultant solid was removed by suction filtration and the filtrate (pH 8-9) was extracted three times with EtOAc. The combined organic fractions were dried over MgSO4, filtered, and concentrated to afford 0.069 g of a 5:1 mixture (determined by 1H NMR) of ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine and recovered
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:13])=[CH:5]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
5-Chloroindole-2-carboxylic acid (391 mg, 2 mmol), tert-Butyl [(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]carbamate (497 mg, 2 mmol), DIPEA (350 μL, 2 mmol) and HOBT (270 mg, 2 mmol) were dissolved in DCM (10 mL), stirred for 5 mins, then EDCI (479 mg, 2.5 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (25 mL) was added and the organic solution washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (800 mg, 94%) as a pale brown foam.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N)c(C#N)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Temperature: 55 °C
Reaction time: 22 h
Yield: 57.1 %

Procedure:
Combine 1-fluoro-2-nitro-benzene (4.34 g, 30.79 mmol), 2-amino-5-methyl-benzonitrile (4.07 g, 30.79 mmol), lithium hydroxide monohydrate (2.58 g, 61.58 mmol) and DMSO (50.0 ml). Stir the mixture at 55° C. for 22 hours then cool it to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dry the precipitate under vacuum then purify it on silica gel using dichloromethane/hexanes (75:25) to give 4.45 g (57%) of an orange solid: mp 135–139°; mass spectrum (ion spray): m/z=254.0 (M+1).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19]C(Cl)Cl.Cl>ClCCl>[CH:18]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4]2)=[O:19]
Reactant: COC(Cl)Cl
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCC(C(=O)O)O2
Temperature: -30 °C
Yield: 32.6 %

Procedure:
A solution of the compound from Example 9 (11.5 g, 64.5 mmol) in dichloromethane (60 mL) was added to a cooled (−10° C.) mixture of aluminum chloride (21.5 g, 161 mmol) in dichloromethane (30 mL). The mixture was cooled to −30° C. for 20 minutes and dichloromethyl methyl ether (11.7 mL, 129 mmol) was added dropwise over one hour. After an additional 45 minutes the mixture was poured into a mixture of ice (325 mL) and concentrated HCl (5 mL). The mixture was filtered and the filtrate removed. The collected solids were dissolved in tetrahydrofuran. The tetrahydrofuran solution was dried (MgSO4) and concentrated to give a solid. The solid was washed with dichloromethane (3×25 mL) and dried in vacuo at room temperature to give a light pink solid (4.34 g, 33%). 1H NMR (300 MHz, DMSO-d6) δ 13.17 (br s, 1H), 9.81 (s, 1H), 7.64 (m, 2H), 6.99 (d, J=9.2 Hz, 1H), 4.94 (t, J=5.0 Hz, 1H), 2.87 (m, 1H), 2.14 (m, 2H); MS (FAB) m/z 207 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH:12]([CH2:15]Cl)[C:13]#[N:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[C:13](=[NH:14])[C:12](=[CH2:15])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(CCl)NC(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C1NC(=O)N(Cc2ccccc2)C1=N

Procedure:
A solution of 4.75 g. (20 mmol) 2-(benzylaminocarbonylamino)-3-chloropropionitrile and 6 ml. triethylamine in 50 ml. dry tetrahydrofuran is heated to reflux for 5 hours. Subsequently, the precipitate formed is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel (elution agent: ethyl acetate) to give 2.5 g. (62.2% of theory) of the title compound; m.p. 139°-141° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[C:10]1([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC)=O)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)([CH:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:22][CH2:21]2)[OH:25])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 70 parts of 1-bromo-4-fluorobenzene and 10 parts of magnesium in 270 parts of tetrahydrofuran, was added dropwise a solution of 25 parts of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate in 90 parts of tetrahydrofuran. Upon completion, stirring was continued for 2 hours at reflux temperature. The reaction mixture was cooled and poured onto a saturate ammonium chloride solution. The organic phase was separated, dried, filtered and evaporated, yielding 40 parts of α,α-bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol as a residue (intermediate 12).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-fluorophenyl)piperazine (215 mg, 1.2 mmol), and DIEA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.77 (m, 4H) 3.10 (m, 4H) 4.06 (s, 2H) 7.08 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 329 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)#N.[CH2:8]([Mg]Br)[CH2:9][CH3:10].S(=O)(=O)(O)[OH:14].[OH-].[Na+]>C1COCC1.O>[NH:6]1[CH:7]=[C:3]([C:1](=[O:14])[CH2:8][CH2:9][CH3:10])[N:4]=[CH:5]1
Reactant: CCC[Mg]Br
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)c1c[nH]cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of 4-cyanoimidazole (2 g, 21.4 mmol) in THF (25 ml) was added dropwise to a solution (68.5 mL, 68.5 mmol, 3.2 equivalents) of 1 M n-propyl magnesium bromide in THF at 0 to 10° C. under a nitrogen atmosphere. The mixture was stirred at 15 to 25° C. for 4 h. Water (20 ml) and 10% aqueous sulfuric acid solution (45 ml) were successively added dropwise, and the mixture was stirred at 1 h. A 30% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 8. After partitioning, the aqueous layer was extracted with ethyl acetate (15 ml×2). The organic layer was combined, and the mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, and concentrated under reduced pressure. The concentration residue was broken up with n-hexane (12 ml), and the crystals were collected by filtration and washed with n-hexane. The crystals were dried in vacuo (40° C.) to give 1-(1H-imidazol-4-yl)-1-butanone (2.45 g, yield 83%). 1H-NMR (CDCl3): δ 0.90 (3H, t, J=7.4 Hz), 1.60 (2H, q, J=7.3 Hz), 3.34 (2H, q, J=7.1 Hz), 7.77 (1H, s), 7.85 (1H, s)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)C=O.[H-].[Na+].[Cl:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30]>C(Cl)Cl>[ClH:13].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][S:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: ClCc1ccccc1SCc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: Clc1ccc(CSc2ccccc2Cc2ncc[nH]2)c(Cl)c1
Reaction time: 1.5 h

Procedure:
2.72 g. of imidazole in 50 ml. of dimethylformamide is combined with 1.2 g. of sodium hydride suspension (80% strength). After allowing the mixture to stand at room temperature for 1.5 hours, 12.7 g. of (2-chloromethylphenyl)-(2,4-dichlorobenzyl)-sulfide is added thereto (prepared analogously to J. Org. Chem. 30 [1965] 4074), and the mixture is agitated for 20 hours at room temperature. After working up the mixture as indicated in Example 2, 12.5 g. of (2,4-dichlorobenzyl)-[2-(1-imidazolylmethyl)-phenyl]-sulfide, hydrochloride, is obtained by recrystallization from methylene chloride, m.p. 171°-175°.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=O)[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1.Cl.[NH2:34][OH:35]>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=[N:34][OH:35])[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1
Reactant: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=O)CCC2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCCCN(CCCC)CCCC
Product: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=NO)CCC2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Tributylamine (6.6 mL 28 mmol) was added to a stirred suspension of 3-(4-chlorophenylsulfanyl)-2-methyl-4,5,6,7-tetrahydro-1H-indol-4-one (8.0 g, 27 mmol) and hydroxylamine hydrochloride (1.9 g, 27 mmol) in ethanol (40 mL). The mixture was heated to 65° C. and maintained at this temperature for 4 h then allowed to cool to r.t. and left overnight. Additional hydroxylamine hydrochloride (0.15 g, 2.2 mmol) and tributylamine (1.0 mL, 4.2 mmol) were added and the mixture was re-heated to 65° C. for a further 2 h. After cooling to r.t., the solid product was collected by filtration, washed with ethanol (2×10 mL) then dried in a vacuum oven at 40° C. to give the title compound as an off-white solid; 5.71 g (68%); purity: 96.3 area % by HPLC; m/z: 307/309 (MH+); 1H-NMR: 11.26 (1H, s), 10.20 (1H, s), 7.23 (2H, m), 6.92 (2H, m), 2.62-2.58 (2H, m), 2.56-2.52 (2H, m), 2.12 (3H, s), 2.83-1.76 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:18])[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32]C(=O)C)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[OH-].[K+].C(O)C.C(O)(=O)C>O>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[O:18])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCOC(C)=O)CC2)nc1N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCO)CC2)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A suspension of acetic acid 3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester (25 mg, 0.049 mmol, Example 274) in a solution of potassium hydroxide (50 mg, 0.9 mmol), water (1 mL) and ethanol (6 mL) was stirred at 25° C. for 1 hour. The solution was cooled, acidified with acetic acid and reduced in volume to 2 mL. This was diluted with water and the product extracted into methylene chloride. After washing with water, the organic layer was separated and dried (Na2SO4). The residue was purified by silica gel chromatography (ethyl acetate) and crystallized from methylene chloride/hexane to give [4-amino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanoneas a white solid (12 mg, 50% yield). HRMS, observed: 468.1716; Calcd for (M+H)+: 468.1712
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[Br:22]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.[Fe]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[C:5]([Br:22])=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: BrBr
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1nc(N)nc(-c2ccc(F)c3ccccc23)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (free base, 0.100 g) in carbon tetrachloride (10 mL) was added iron powder (0.002 g) and bromine (0.074 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, after which time it was poured into sodium bicarbonate solution (saturated, 30 mL). The layers were separated and the aqueous layer was extracted three times with methylene chloride (3×10 mL). The combined organic layers were evaporated to dryness. The residue was purified by preparative thin layer chromatography, eluting with hexane/ethyl acetate, and recrystallized from ether/hexane to give 2-amino-5-bromo-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.072 g), m.p. 176-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=3[NH:12][C:11](=[O:20])[CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[CH2:25][S:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:21])[CH2:10][C:11](=[O:20])[NH:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]2=3)=[CH:4][CH:3]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(NS(=O)(=O)Cc2ccccc2Cl)cc1
Yield: 95.9 %

Procedure:
By using 1-(4-aminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (20 mg, 0.071 mmol), and 2-chlorobenzylsulfonyl chloride (19 mg, 0.084 mmol), the title compound (32 mg, yield 96%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.O.[Br:16]Br.S([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[Br:16][C:2]1[C:1](=[O:14])[C:13]2[C:5](=[CH:4][CH:3]=1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=2
Reactant: BrBr
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C(Br)=CC=C2C1=Cc1ccccc12
Reaction time: 12 h
Yield: 92.9 %

Procedure:
In a three-liter flask having four openings equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, respectively, 256 g (1.4 mol) of fluorenone, 1 L of water, three drops of a surfactant, and five drops of sulfuric acid were placed and stirred to mix. By adding 250 g (1.6 mol) of bromine into the mixture, a reaction was started. After the reaction had been conducted at 50° C. for 12 hours, unreacted bromine was decomposed with an aqueous solution of sodium hydrogen sulfite. The reaction product, which was a dark yellow solid, was filtered and thus 365 g of a crude product was obtained. The crude product was dissolved in toluene and was subsequently washed with water and a sodium hydrogencarbonate aqueous solution. The resulting organic liquid was dried using anhydrous magnesium sulfate. After filtration, the liquid was concentrated and then allowed to stand at 0° C., so that a yellow solid was precipitated. The precipitate was filtered and subsequently washed with toluene, followed by drying. Thus, 339 g (1.3 mol, yield of 92%) of a yellow solid product was obtained. This product was subjected to gas chromatography and the purity of the product was 99.4%.