Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14](Br)[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1.[CH3:24][Sn](C)(C)C.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14]([CH3:24])[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1
Reactant: C[Sn](C)(C)C
Reactant: Cc1c(Br)c(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(C)c(-c2ccc3c(c2)C(C)(C)OC(=O)N3)n(C)c1C#N
Yield: 85.8 %

Procedure:
A solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile (0.11 g, 0.29 mmol), PhCNPdCl(PPh3)2 (cat., 11 mg) and tetramethyltin (10 eq, 0.53 g, 2.9 mmol) in HMPA (3 mL) was heated to 110° C. for 5 days. The solution was allowed to cool, poured into water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile (77 mg, 85%) as a white solid. 1H NMR (300 MHz, d6-DMSO): δ 1.63 (s, 6H), 1.87 (s, 3H), 2.49 (s, 3H), 3.50 (s, 3H), 6.99 (d, 1H, J=8.2 Hz), 7.25 (dd, 1H, J=8.2, 1.4 Hz), 7.29 (s, 1H), 10.39 (s, 1H). MS (ESI (−)) 308 (M−H)−. Anal. calcd for C18H19N3O4, C, 69.9, H, 6.19; N, 13.6. Found, C, 68.8, H, 6.22; N, 12.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([CH:30]=1)[CH2:7][C@@H:8]1[CH2:14][N:13]([CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])[C:12](=O)[CH2:11][NH:10][C:9]1=[O:29].O1CCCC1.C1C=CC(OC2C=CC(P3(SP(C4C=CC(OC5C=CC=CC=5)=CC=4)(=S)S3)=[S:52])=CC=2)=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([CH:30]=1)[CH2:7][C@@H:8]1[CH2:14][N:13]([CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])[C:12](=[S:52])[CH2:11][NH:10][C:9]1=[O:29]
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)NCC2=O)c(OC)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)NCC2=S)c(OC)c1
Reaction time: 3 h
Yield: 124.3 %

Procedure:
To the compound S140c described in WO 06-059801A, that is, (6R)-6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,4-diazepane-2,5-dione (2.2 g) in a tetrahydrofuran (80 ml) solution, Belleau's reagent (1.5 g) was added under ice cooling, and the mixture was stirred at that temperature for 3 hours. The reaction solution was diluted with ethyl acetate, successively washed with saturated aqueous sodium hydrogencarbonate solution, water, and brine, dried over anhydrous sodium sulfate, then concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=35/65 to 1/99) to obtain the title compound (1.69 g).
Reaction SMILES: [SH:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([S:1][CH:2]([CH3:23])[CH:3]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(S)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SC(C)C(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 31.3 %

Procedure:
3-[(3-Mercapto-2-benzylbutanoyl)amino]benzoic acid (compound of Example 194) (1.7 g) is suspended in dichloromethane (17 ml), and thereto is added triethylamine (0.52 g)with stirring under ice cooling. To the mixture are further added dropwise acetyl chloride (0.51 g) and triethylamine (0.52 g) simultaneously, and the mixture is stirred at room temperature for one hour. The reaction mixture is diluted with dichloromethane and washed with 10% hydrochloric acid and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then dichloromethane is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (0.6 g).
Reaction SMILES: [N+:1]([CH:4]([CH3:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].CO>C(OCC)C.CN(C)C1C=CN=CC=1>[C:14]([O:6][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]([N+:1]([O-:3])=[O:2])[CH3:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(O)c1ccccc1)[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCOCC
Product: CC(=O)OC(c1ccccc1)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 2-nitro-1-phenylpropan-1-ol (32 g) and acetic anhydride (22 mL) in diethyl ether (300 mL) was added 4-dimethylaminopyridine (0.61 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Methanol was added to the reaction mixture, and the mixture was further stirred for 30 min and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 34 g, 86%).
Reaction SMILES: C[N:2]([C@@:10]1([CH3:15])[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=O)OC(C)(C)C.C(N(CC)CC)C.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28](F)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:26]=1[CH3:47])#[N:24]>CS(C)=O>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28]([N:12]2[CH2:13][CH2:14][C@:10]([CH3:15])([NH:2][CH3:3])[CH2:11]2)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:26]=1[CH3:47])#[N:24]
Reactant: Cc1c(-c2cccc(F)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@@]1(C)CCN(c2c(-c3cccc(F)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Yield: 21 %

Procedure:
A dimethyl sulfoxide (0.5 ml) solution of the above-mentioned tert-butyl methyl[(3S)-3-methylpyrrolidin-3-yl]carbamate (I-348) and triethylamine (172 μl, 1.23 mmol) was added to a dimethyl sulfoxide (4.5 ml) solution of 4-cyano-7-fluoro-6-(3-fluorophenyl)-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-184) (300 mg, 0.878 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (3 ml), and with cooling with ice, trifluoroacetic acid (6 ml) was added, followed by stirring at room temperature for 8 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with a mixed solvent of isopropyl ether and hexane to obtain the entitled compound (80.0 mg, 21%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:15]([CH3:14])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: COC(=O)CCBr
Reactant: COC(=O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1OC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
A solution of methyl 4-chlorosalicylate (5.0 g) in dimethyl formamide (10 ml) was treated sequentially with methyl 3-bromopropionate (4.0 g) and potassium carbonate (6.0 g). The mixture was stirred at room temperature for 18 hrs and diluted with water. The mixture was extracted with ether and the organics were washed with water. The organic layer was dried and evaporated to give the desired material (6.7 g) as a low melting solid. NMR: 7.8 (d, 1H), 7.2 (m 1H), 6.9 (m, 1H), 4.8 (q, 1H), 3.9 (s, 3H), 3.8 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[C:12]([CH3:27])[N:11]=1)([CH3:9])[CH3:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[O:35])[CH:29]=1>C1COCC1>[CH3:9][C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[C:12]([CH2:27][CH:34]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[OH:35])[N:11]=1)([CH3:6])[CH3:8]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(CC(O)c2cccnc2)nc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
n-Butyllithium (1.5 mL of 1.6M solution in hexane, 2.4 mmol) is added dropwise to a solution of 4,6-bis (1,1-dimethylethyl)-5-[(2-methoxyethoxy) -methoxy]-2-methylpyrimidine (750 mg, 2.4 mmol) in dry THF (12 mL) at 0° C. under an atmosphere of dry nitrogen. The reaction mixture is stirred at room temperature for 30 minutes and then cooled to -78° C. A solution of pyridine 3-carboxaldehyde (250 mg, 2.4 mmol) in dry THF (1 mL) is added dropwise. The reaction mixture is stirred at room temperature for 3 hours and then is quenched by the addition of saturated aqueous ammonium chloride. The product is extracted into ether. The organic layer is dried (MgSO4) and evaporated to give crude 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-α-(3 -pyridinyl)-2-pyrimidineethanol (500 mg, 50%) which is not further purified, but used directly in the next reaction.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([SiH2:11][O:12][C:13]([CH3:32])([CH3:31])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:30])[C:21]2[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=2)[C:26]#[N:27])=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[NH+]1C=CC=CC=1.C1(C)C(S([O-])(=O)=O)=CC=CC=1>ClCCl>[C:7]([SiH2:11][O:12][C:13]([CH3:32])([CH3:31])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:30][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:21]2[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=2)[C:26]#[N:27])=[CH:18][CH:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(O)c2ccc(F)c(C#N)c2)cc1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(OC2CCCCO2)c2ccc(F)c(C#N)c2)cc1
Yield: 97.8 %

Procedure:
Add 3,4-dihydro-2H-pyran (0.340 g, 4.04 mmol) to a solution of 5-{[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-hydroxy-methyl}-2-fluoro-benzonitrile (1.00 g, 2.69 mmol) and pyridiniuM-toluenesulfonate (0.068 g, 0.269 mmol) in dichloromethane (0.2M). Stir the reaction for 3 h at room temperature. Evaporate solvent and filter through a short pad of silica gel. The title compound (1.20 g, 2.63 mmol, 98%) is taken directly onto the next step (Preparation 58). MS (m/z): 456 (M+1).
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[OH:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:2]2[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=2)=[CH:17][CH:18]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(C)c1C#N
Reactant: Nc1ccc(CCO)cc1
Product: Cc1nc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c(C)c1C#N

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 6-chloro-2,4-dimethyl-5-nitronicotinonitrile (step 3) and 4-aminophenylethyl alcohol.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH2:17]Br)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+]>C1COCC1.O>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH2:17][C:11]3[C:10](=[CH:15][C:14]([F:16])=[CH:13][CH:12]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)cccc1N1Cc2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Step 3 A mixture of N-(3-bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide (2.54 g, 6.33 mmol) and sodium tert-butoxide (0.913 g, 9.50 mmol) in THF (80 mL) was stirred at rt for 30 min. The mixture was diluted with water and extracted with twice with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-6-fluoroisoindolin-1-one as a white solid (1.18 g, 58%). 1H NMR (400 MHz, chloroform-d) δ 7.59-7.65 (2 H, m), 7.45-7.50 (1 H, m), 7.33 (1 H, td, J=8.6, 2.5 Hz), 7.19-7.24 (1 H, m), 7.15 (1 H, t, J=7.9 Hz), 4.68 (2 H, s), 2.31 (3 H, s). Mass spectrum m/z 320, 322 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([S:14]C#N)=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(P(CC)CC)C>CC(C)=O.O>[SH:14][C:5]1[CH:4]=[C:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]([OH:1])=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=1
Reactant: N#CSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: CCP(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
2'-Hydroxy[1,1':3',1"-terphenyl]-5'-yl thiocyanate (32.2 g, 0.106 mole) was dissolved in acetone (150 ml) and water (1.9 ml), stirred and cooled to -5° C. Triethylphosphine (15.7 ml, 0.106 mole) was added dropwise over a period of 40 minutes. The reaction was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The solvent was evaporated and the product isolated by chromatography on silica.
Reaction SMILES: [C:1]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11](SC)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.CCN(C(C)C)C(C)C.[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[C:1]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([NH:53][C:52]2[CH:51]=[CH:50][C:49]([N:46]3[CH2:45][CH2:44][N:43]([CH3:42])[CH2:48][CH2:47]3)=[CH:55][CH:54]=2)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1ccccc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Example 3A (200 mg, 0.661 mmol) in dichloromethane (2.2 mL) was added meta-chloroperoxybenzoic acid (179 mg, 0.728 mmol) in a single portion. After 1 hour, the reaction mixture was partitioned between 10% sodium thiosulfate solution and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL). Hunig's base (231 μl, 1.323 mmol) and 4-(4-methylpiperazin-1-yl)aniline (127 mg, 0.661 mmol) were added to the solution, and the reaction was heated to 45° C. for 3 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Compound 86 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried, and the product was purified by column chromatography (eluent 25% EtOAc/hex) to give a solid (0.12 g, 13%): Mp=152-154° C.; 1H NMR (DMSO-d6) δ 10.01 (br s, 1 H), 7.77 (d, 2 H, J=8.9 Hz), 7.32-7.25 (m, 3 H), 6.91 (d, 2 H, J=8.9 Hz); MS 245 [M−H]−
Reaction SMILES: [K].[CH3:2][CH:3]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][S:6]1(=[O:17])=[O:16])[CH3:4].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(#N)C>[CH3:4][CH:3]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])[S:6]1(=[O:17])=[O:16])[CH3:2]
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Reactant: CC(C)(C)C(=O)Cl
Agent: [K]
Solvent: CC#N
Product: CC(C)N1C(=O)c2ccccc2N(C(=O)C(C)(C)C)S1(=O)=O

Procedure:
To 100 ml of acetonitrile was added 11.6 g of the potassium salt of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide. To the resultant stirred mixture was added dropwise 5.4 ml of trimethylacetyl chloride in 50 ml of acetonitrile over a 0.5 hour period. The resultant mixture was heated at 38°-40° C. for 22 hours, cooled, filtered and the solvent removed from the filtrate in vacuo. The residue was dissolved in 100 ml of ether and extracted with 100 ml of 5% potassium carbonate. The ether layer was washed once with 100 ml of water, dried with magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo and the solid residue, 8.3 g, extracted with 3-10 ml-portions of methanol. The resultant precipitate was air dried to afford 4.5 g of 3-(1-methylethyl)-1-(2,2-dimethyl-1-oxopropyl)-1H- -2,1,3-benzothiadiazin-4 (3H)-one-2,2-dioxide, m.p. 97.5°-99.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccc2ncccc21
Product: O=C(Cn1c(=O)ccc2ncccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (42 mg, 0.204 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.101 mmol) according to protocol A. Retention time (min)=2.295, method [7], MS(ESI) 431.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.57 (dd, J=4.6, 1.7 Hz, 1H), 8.16 (d, J=9.9 Hz, 1H), 8.11 (s, 1H), 7.98 (d, J=9.1 Hz, 1H), 7.62 (dd, J=8.8, 5.1 Hz, 1H), 7.01 (d, J=4.3 Hz, 1H), 7.05 (s, 1H), 5.33 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1>CN1CCCC1=O.C(OCC)(=O)C>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)[CH2:20]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 1-(4-chloro-2-nitrophenyl)ethanone (WO 9322287) (700 mg, 3.5 mmol) and cis-2,6-dimethylpiperazine (1.2 g, 10.5 mmol) in 1-methyl-2-pyrrolidinone (12 ml) was heated at 160° C. in a microwave reactor for 40 min. The reaction mixture was cooled, diluted with ethyl acetate and washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting 1:1 mixture of the title compound (D5) MS (ES+) m/e [M+H]+278 and 1-[4-chloro-2-(cis-3,5-dimethyl-1-piperazinyl)phenyl]ethanone MS (ES+) m/e [M+H]+267/269 was used crude in the next reaction.
Reaction SMILES: [NH2:1][C@@:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:6][C@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10].[C:18]1([CH2:31][O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[C:30]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>ClCCl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C@:2]1([NH:1][C:36]([NH:35][C:33](=[O:34])[O:32][CH2:31][CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:30][C:29]=3[C:28]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:37])[CH2:6][C@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10]
Reactant: O=C(N=C=S)OCc1cccc2c1Cc1ccccc1-2
Reactant: CO[C@@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Solvent: ClCCl
Product: CO[C@@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Yield: 62.5 %

Procedure:
A solution of [(1R*,2S*,4R*)-2-amino-2-(2-fluorophenyl)-4-methoxycyclopentyl]methanol (250 mg) and fluorenylmethyloxycarbonyl isothiocyanate (351 mg) in dichloromethane (20 mL) was stirred at room temperature for three days. The reaction solution was purified by silica gel column chromatography to obtain the title compound (340 mg).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@@H:11]([C@@H:19]([OH:22])[CH2:20][CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[C:23]([N:27]=[C:28]=[S:29])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([NH:27][C:28]([NH:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C@@H:19]([OH:22])[CH2:20][CH3:21])=[S:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=S
Reactant: CC[C@H](O)[C@H](N)Cc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=S)NC(C)(C)C
Temperature: 50 °C

Procedure:
4.3 cm3 of triethylamine are added to a solution of 3.6 g of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride in 60 cm3 of ethanol, followed by addition of 2.6 cm3 of tert-butyl isothiocyanate. The mixture is heated at a temperature in the region of 50° C. for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and the residue is taken up in 50 cm3 of water and 100 cm3 of dichloromethane. The organic phase is washed with 30 cm3 of water, dried over sodium sulphate, filtered and concentrated under the above conditions. 4.3 g of N-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea are obtained in the form of a thick colourless oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.80 (t, J=7.5 Hz: 3H); from 1.25 to 1.55 (mt: 2H); 1.37 (s: 9H); 2.72 (dd, J=14 and 9 Hz: 1H); 2.93 (dd, J=14 and 4.5 Hz: 1H); 3.37 (mt: 1H); 4.60 (mt: 1H); 4.88 (unresolved complex: 1H); 7.11 (s: 1H); 7.16 (d, J=8.5 Hz: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 8.43 (broad d, J=5.5 Hz: 2H)].