Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[C:15]1[C:28](=[O:29])[N:27]([CH3:30])[C:18]2[N:19]=[C:20](S(C)(=O)=O)[N:21]=[CH:22][C:17]=2[CH:16]=1.[N:31]1[S:32][N:33]=[C:34]2[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][C:35]=12>CS(C)=O.O.C(OCC)(=O)C>[N:31]1[S:32][N:33]=[C:34]2[CH:39]=[C:38]([NH:40][C:20]3[N:21]=[CH:22][C:17]4[CH:16]=[C:15]([C:9]5[C:8]([Cl:7])=[CH:13][CH:12]=[CH:11][C:10]=5[Cl:14])[C:28](=[O:29])[N:27]([CH3:30])[C:18]=4[N:19]=3)[CH:37]=[CH:36][C:35]=12
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc2nsnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4nsnc4c3)nc21

Procedure:
184 mg of potassium tert-butoxide are added in three installments, at ambient temperature under argon, to 300 mg of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 170 mg of the compound of formula (III), 2,1,3-benzothiadiazol-5-ylamine, in suspension in 5 ml of DMSO. After a contact time of 30 minutes, the reaction medium is diluted with a mixture of water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are then washed with water and then with a saturated NaCl solution. After drying over Na2SO4 and filtering, the solvent is evaporated and then the residue is taken up in a few milliliters of ethyl acetate. The green precipitate obtained is filtered off and then chromatographed on silica (gradient: DCM 100 to DCM/MeOH 90:10). 105 mg of the expected product are isolated in the solid form.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][NH:12][C@@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH:35]1[C:40]2[C:41]([O:43][C:44](=[O:45])[C:39]=2[CH:38]=[C:37]2[C:46]([O:48][C:49](=[O:50])[C:36]=12)=[O:47])=[O:42].C([O-])([O-])=[O:52].[Na+].[Na+]>C1COCC1>[N:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][N:12]([C@@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)[C:41]([C:40]2[CH:35]=[C:36]([C:49]([OH:48])=[O:50])[C:37]([C:46]([OH:52])=[O:47])=[CH:38][C:39]=2[C:44]([OH:43])=[O:45])=[O:42])=[CH:5][CH:6]=1
Reactant: c1cc(CN[C@H]2CCCc3ccccc32)cc(Oc2ccncc2)c1
Reactant: O=C([O-])[O-]
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Oc3ccncc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 106A (1.17 g), diisopropylethyl amine (2.5 mL, 14.4 mmol) and 1,2,4,5-benzenetetracarboxylic dianhydride (0.78 g, 3.58 mmol) in THF (30 mL) were processed as described in Example 1B. The reaction mixture was treated with saturated Na2CO3 solution (30 mL), and stirred vigorously at room temperature for 1 hour. The layers were separated and the aqueous layer was acidified with 1N HCl. The acidified aqueous layer was evaporated under reduced pressure to afford off-white plates. Soxhlet extraction (ethanol) of the crude solid, followed by RP-HPLC, provided the title compound (20 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.[CH3:19][NH:20][CH2:21][CH2:22][C:23]#[N:24]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:20]([CH3:19])[CH2:21][CH2:22][C:23]#[N:24]
Reactant: BrCc1cccc(Br)c1
Reactant: CNCCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCC#N)Cc1cccc(Br)c1
Reaction time: 16 h
Yield: 116.9 %

Procedure:
Hunig's base (26.5 mL, 0.15 mol) was added to 3-bromobenzyl bromide (38 g, 0.15 mol) and N-methyl-β-alanine nitrile (14.2 mL, 0.15 mol) in dry DMF (400 mL). The solution was stirred 16 h, concentrated in vacuo to near dryness, triturated with ether/EtOAc, and filtered. [A second reaction was repeated on 12 g]. The combined filtrates were concentrated by rotory evaporation and the residue was charged (CH2Cl2) to a 65 (M) Biotage® silica gel column; Segment 1: Gradient elution from 5-15% B over 1.3 L; Segment 2: 15%-100% B (A=Hexanes; B=EtOAc) over 6.75 L to give Example 4, 3-((3-bromobenzyl)(methyl)amino)-propanenitrile 44.4 g (88%). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H), 3.54 (s, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 2.17 (s, 3H). RT=1.1 minutes (condition 2); LRMS: Anal. Calcd. for C11H13BrN2: 253.03. found: 253.05 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1)=O.Cl.[OH:21][NH2:22]>C(O)C.O>[OH:21][N:22]=[CH:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1C(=O)NCc1ccccn1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a solution of 0.50 g of 4-formyl-2-methyl-N-(2-pyridylmethyl)benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.18 g of hydroxyamine hydrochloride was added with stirring at room temperature, and stirred at the same temperature for 12 hours. After the completion of the reaction, solid was filtered off, ethanol was distilled off under reduced pressure, and 30 ml of saturated sodium hydrogen carbonate aqueous solution was added in the remaining aqueous solution. The precipitated crystal was filtered off, washed with water and dried to obtain 0.45 g of the aimed product as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:27](Cl)(=[O:29])=[O:28].[NH3:31].Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:27](=[O:29])(=[O:28])[NH2:31]
Reactant: N
Reactant: O=C(Nn1cc(S(=O)(=O)Cl)c2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 8 %

Procedure:
A solution of 5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonyl chloride (0.14 g) in DCM (20 mL) is treated with a solution of aqueous ammonia solution (28%-5 mL) in water (15 mL) and stirred at rt for 24 h. The reaction mixture is acidified with 10 N aqueous HCl to pH ˜3 and extracted with DCM. The organic layer is washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 50% EtOAc in heptane to afford 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid-[5-fluoro-3-sulfamoylindol-1-yl)amide (10 mg, 8%) as a solid. MS: 430 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 7.20-7.30 (m, 1H), 7.40-7.50 (m, 2H), 7.60-7.72 (m, 2H), 8.10 (s, 1H), 8.19-8.22 (d, 1H), 8.33-8.37 (d, 1H), 9.44 (s, 1H), 12.45 (s, 1H).
Reaction SMILES: Cl.Cl.CN([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[CH2:12]([N:14](CC)[CH2:15]C)C.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]([OH:31])=O)=[CH:21]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:12][N:14]([CH3:15])[CH:10]1[CH2:9][CH2:8][CH2:7][N:6]([C:29]([C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]([CH3:19])[CH:21]=2)=[O:31])[CH2:11]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: CCN(CC)CC
Reactant: CN(C)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C1CCCN(C(=O)c2cn(C)c3ccccc23)C1
Reaction time: 0.25 h

Procedure:
A mixture of 3 dimethylaminopiperidine dihydrochloride (18 g; 0.01 mol), triethylamine (2.5 g) and dichloromethane (50 ml) was stirred for 15 min. 1-Methylindole-3-carboxylic acid (2.1 g, 0.012 mol) was then added, followed by dicyclohexylcarbodiimide (2 5 g). The mixture was stirred for 48h, filtered and extracted with 1M hydrochloric acid (20+10+10 ml). The acid extracts were basified with ammonia and back extracted to chloroform. The chloroform extract was dried, evaporated and the residue dissolved in IPA (25 ml), then acidified with ethanolic hydrogen chloride to precipitate the hydrochloride 2.55 g, mp 250-251° C.
Reaction SMILES: C([Li])#[C:2][CH3:3].[C:5]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:37])[C:20]([C:22]2[C:30]3[C:25](=[C:26]([C:31]4[CH:36]=NC=CN=4)[CH:27]=[CH:28][N:29]=3)[NH:24][CH:23]=2)=[O:21])[C@H:15]([CH3:38])[CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:39]1CCCC1>>[C:5]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:37])[C:20]([C:22]2[C:30]3[C:25](=[C:26]([C:31]([CH2:36][C:2]#[CH:3])=[O:39])[CH:27]=[CH:28][N:29]=3)[NH:24][CH:23]=2)=[O:21])[C@H:15]([CH3:38])[CH2:14]1)(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: [Li]C#CC
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(-c3cnccn3)ccnc12
Product: C#CCC(=O)c1ccnc2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)C[C@H]3C)c[nH]c12

Procedure:
Propynyllithium (21 mg) was added to a solution of Example 52 (41 mg) in tetrahydrofuran (5 ml) at −78° C. The reaction was quenched with methanol at −25° C. in 2 hours. After solvents were removed under vaccum, the residue was carried to the further reactions without any purification. I-64, 1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine MS m/z: (M+H)+ Calc'd for C25H22ClN4O4: 477.13; found 477.17. HPLC retention time: 1.46 minutes (column A).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Br)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
6-Bromo-pyridin-2-carbaldehyde (5.0 g, 26.9 mmol), malonic acid (6.3 g, 60.5 mmol), and piperidine (2.2 mL, 22.4 mmol) were added to pyridine (16.3 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 4.5 g of the titled compound as a brown solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([S:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[CH:9][N:10]=1>C(O)C>[CH2:1]([O:3][C:14](=[O:15])[C:13]([CH3:17])([CH3:18])[CH2:12][S:11][C:8]1[S:7][C:6]([NH2:5])=[N:10][CH:9]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(CSc1cnc(N)s1)C(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Reaction time: 0.5 h

Procedure:
Acetyl chloride (3.0 eq) was added drop wise to ethanol and stirred for additionally 30 min after completed addition. 3-(2-Amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid was added neat to this solution and the mixture was stirred at 50° C. for 18 h. The mixture was concentrated under reduced pressure and diluted with ethyl acetate and water. The strongly acidic solution was added NaHCO3 (aq; sat) to pH=8. The phases were separated and the aqueous phase extracted with additional ethyl acetate. The combined org. phases were washed with water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to give 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester as brown crystals.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:7]2[C:11]([O:13]CC1C=CC([N+]([O-])=O)=CC=1)=[O:12])[CH3:2].C(=O)(O)[O-].[Na+:35]>O1CCOCC1.O.[Pd]>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:7]2[C:11]([O-:13])=[O:12])[CH3:2].[Na+:35]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Oc3ccccc3)SC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC1C(=O)N2C(C(=O)[O-])=C(Oc3ccccc3)SC12
Yield: 96.5 %

Procedure:
A mixture of a solution of 306 mg of 4-nitrobenzyl 6-ethyl-3-phenoxy-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 60 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes. The mixture was then filtered through Celite, and lyophilised to yield 216 mg of the title compound as a pale yellow crystalline solid (96% of the theoretical yield).
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][C@H:13]2[CH2:17][C@H:16]([C:18](=[O:33])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C:27]4=[O:32])=[CH:22][CH:21]=3)[N:15]([C:34](=[O:43])[NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH2:14]2)=O)=CC=1)([O-])=O>CO>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:34]([N:15]2[CH2:14][C@@H:13]([OH:12])[CH2:17][C@@H:16]2[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)=[O:33])=[O:43])=[CH:37][CH:38]=1
Reactant: O=C(O[C@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
8.1 5.51 ml (35 mmol) of diethyl azodicarboxylate (DEAD) are added dropwise at 0° C. under nitrogen to a solution of 7.0 g (7.26 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-(4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate, 5.77 g (34.5 mmol) of p-nitrobenzoic acid and 9.18 g (35 mmol) of triphenylphosphine in 350 ml of tetrahydrofuran. The reaction mixture is subsequently left to stir at room temperature for 12 hours and evaporated to dryness-under reduced pressure, 20 ml of methylene chloride are added to the residue, and the methylene chloride solution is washed successively with 10 ml of saturated sodium chloride solution and 10 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the solvent has been stripped off in a rotary evaporator, the residue is triturated with 30 ml of diethyl ether, giving 8.5 g (88.8%) of tert-butyl-(2R,4S)-4-(4-nitrobenzoyloxy)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as slightly yellow crystals, ESI 555. 8.2 Analogously to Example 7, reaction of tert-butyl (2R,4S)-4-(4-nitro-benzoyloxy)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate gives the compound (3S,5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl 4-nitrobenzoate as yellowish crystals, ESI 608. 8.3 0.075 ml of 1N sodium hydroxide solution is added with ice cooling to the solution of 50 mg (0.082 mmol) of (3S,5R)-1-(4-chlorophenyl-carbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl 4-nitrobenzoate in 2 ml of methanol, and the reaction mixture is stirred for 15 minutes. The precipitate is filtered off and washed with 2 ml of methanol and dried, giving 35 mg (93%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide as colourless crystals, ESI 459, m.p. 243° (decomposition).
Reaction SMILES: [P:1](=[O:10])(Cl)([S:5][CH2:6][CH2:7][CH3:8])[O:2][CH2:3][CH3:4].[C:11]1([S:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.P([S-])(=S)([O-])[O-]>C(#N)C>[P:1]([S:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[CH:26][CH:25]=1)(=[O:10])([S:5][CH2:6][CH2:7][CH3:8])[O:2][CH2:3][CH3:4]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: O=S(=O)(Oc1ccc(S)cc1)c1ccccc1
Agent: [O-]P([O-])(=S)[S-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCSP(=O)(OCC)Sc1ccc(OS(=O)(=O)c2ccccc2)cc1
Temperature: 4 °C

Procedure:
A solution of 5.47 g. (0.026 mole) of O-ethyl S-n-propyl phosphorochloridothioate in 20 ml. of acetonitrile is charged in one portion to a solution of 6.65 g. (0.025 mole) of 4-(benzenesulfonyloxy)thiophenol in 200 ml. of acetonitrile. The solution is stirred and cooled to 4° C. while 2.53 g. (0.025 mole) of triethylamine in 20 ml. of acetonitrile is added dropwise over a 30 minute period. The mixture is held at 5° C. for an additional hour and then concentrated in vacuo. The residue, a mixture of oil and solid, is taken up in 200 ml. of benzene and filtered to remove amine hydrochloride. The filtrate is washed once with 50 ml. of 5% sodium bicarbonate, once with 30 ml. of water, once with 30 ml. of saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo to give 9.1 g. (84%) of the phosphorodithioate as a pale yellow oil. Anal. calc. (found): C 47.2 (47.3); H 4.8 (5.15).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CN1CCCC1
Temperature: 63 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in MeOH (14 mL) and THF (28 mL) was added pyrrolidine (242 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. Then the mixture was concentrated under reduced pressure and dichloromethane (15 mL) was added. The mixture was washed with brine and the organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 318 mg (27%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(pyrrolidin-1-ylmethyl)-benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [NH2:1][OH:2].CO.[CH:5]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:38])[N:27]([CH:29]([C:34]([NH:36][CH3:37])=[O:35])[C:30](OC)=[O:31])[CH3:28])=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:6]1.C(OCC)(=O)C>O>[CH:5]1([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:27]([CH3:28])[CH:29]([C:34]([NH:36][CH3:37])=[O:35])[C:30]([NH:1][OH:2])=[O:31])=[O:38])=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH2:7][CH2:6]1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(CNC3CC3)cc2)cc1
Reactant: NO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(CNC3CC3)cc2)cc1
Reaction time: 0.42 h
Yield: 23 %

Procedure:
A 50% aqueous solution (2.0 mL) of hydroxylamine was added, under ice cooling, to a methanol (4.0 mL) solution of 1-[(cyclopropylamino)methyl]-4-[(1E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-1-en-3-yn-1-yl]benzene (0.18 g) as obtained in Example 23-(4), and the mixture was stirred for 25 minutes under ice cooling and then stirred for 1.5 hours under water cooling. Ethyl acetate and water were added to the reaction mixture to isolate the organic layer, and the extract was washed with water. The washed extract was dried over anhydrous sodium sulfate, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=50/1→10/1), and further purified by preparative silica gel thin-layer chromatography (chloroform/methanol=10/1) to obtain 2-[({4-[(3E)-4-{4-[(cyclopropylamino)methyl]phenyl}but-3-en-1-yn-1-yl]phenyl}carbonyl)(methyl)amino]-N-hydroxy-N′-methylpropanediamide (Compound 481, light yellow solid) (41 mg, 23%).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1([PH2:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]1[CH2:17]OC[CH2:14]1>C(OCC)C>[CH2:4]([C@@H:3]1[CH2:2][C@@H:14]([CH2:13][CH3:17])[P:12]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: Pc1ccccc1
Solvent: CCOCC
Product: CC[C@@H]1C[C@@H](CC)P1c1ccccc1
Temperature: -30 °C

Procedure:
A solution of n-BuLi in hexanes (88 ml of 2.5 N solution), diluted with diethyl ether (400 ml), was added over 3 hours to a stirred mixture of phenylphosphine (10.0 g, 90.1 mmol) and the cyclic sulfate (4S,7S)-4,7-diethyl-2,2-dioxo-1,3,2-dioxathian (19.6 g, 0.1 mol, 10% excess) in of THF (1 L), under a nitrogen atmosphere. The mixture was maintained at a temperature of −30° C. during the first half of the addition period, with cooling to −75° C. for the second half. The mixture was then left to warm overnight. After removal of the solvent, pentane (250 ml) and water (100 ml) were added to the residue. The organic layer was dried, and the solvent was removed to leave the phosphetane as a pale yellow oil which was pure with the exception of a small amount of unreacted phenylphosphine as impurity. After distillation (bp.=81° C. at 0.05 mm), 9.94 g of (2R,4R)-2,4-diethyl-1-phenylphosphetane (53% yield based on phenylphosphine) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[C:21]([F:27])[CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([O:26][CH2:2][C:3]2[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=2)=[C:21]([F:27])[CH:20]=1)[CH3:14]
Reactant: CCCSc1ncccc1CCl
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CCCSc1ncccc1COc1c(F)cc(CCC(=O)OCC)cc1F
Yield: 79 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.1 g, 0.49 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (0.155 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1)[S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][CH2:6]2.S(C1C=CC(C)=CC=1)(O[CH2:43][CH2:44][Cl:45])(=O)=O.[H-].[Na+]>CC(=O)CC>[Cl:45][CH2:44][CH2:43][O:36][C:34]1[CH:35]=[C:30]([CH:21]([S:22][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OCCCl)c1)CC2
Temperature: 25 °C

Procedure:
To a stirred solution of 5.57 g of 5-[7-(3,4-dihydro-6,7-dimethoxy-2 (1H)-isoquinolinyl)-1-[(4-methylphenyl)thio]heptyl]-2-methoxyphenol and 2.0 mL of 2-chloroethyl tosylate in 50 mL of 2-butanone is added 0.44 g of 60% sodium hydride in oil. The solution is heated to reflux for 48 hours and then cooled to room temperature. The solution is partitioned between chloroform and brine and the organic layer dried. The solvent is removed at reduced pressure and the residue chromatographed on silica gel with a gradient elution going from hexane to chloroform to methyl alcohol. The desired fractions are concentrated, dissolved in diethyl ether and passed through a short hydrous magnesium silicate pad. The solvent is removed at reduced pressure to afford 1.6 g of the desired product as a light tan gum.