Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)CCCCC(O)CCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC(CCCl)CCCCC(=O)O
Reaction time: 0.5 h

Procedure:
The methyl ester of (-)-8-chloro-6-hydroxy-octanoic acid (-)-(VIII), (R=Me) (2.1 g, 10 mmoles) and 1.0 g (10 mmoles) of triethylamine were mixed in 40 ml of toluene. While cooling to an internal temperature of 10° to 15° C., 1.4 g (12 mmoles) of methanesulfonyl chloride were added slowly. Stirring was continued for 30 minutes. After the addition of 25 ml of water, stirring was continued for a further 30 minutes, after which the organic phase was removed and dried over magnesium sulfate. The solvent was then evaporated under vacuum. The methyl ester of (-)-8-chloro-6-methanesulfonyloxy-octanoic acid (-)-(II), (R=R'=Me) was obtained in a yield of 2.5 g (88% of the theoretical yield). [α]D20 =-31.3 (c=1; ethanol).
Reaction SMILES: [Cl:1]CC=C(C)CCC=C(C)CCCC(C)C.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>C1(C)C=CC=CC=1>[Cl-:1].[C:30]1([PH+:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=CCCl)CCC=C(C)CCCC(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: [Cl-]
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Yield: 87 %

Procedure:
An amount of 9.1 grams (37 mmol) of 1-chloro-3,7,11-trimethyl-dodeca-2,6-diene and 9.8 grams (37 mmol) of triphenyl phosphine were heated to boiling in 30 ml of toluene for a period of five hours. The resultant suspension was mixed with 200 ml of hexane and after precipitation of the white solid material, the liquid was decanted. This mixing with hexane was repeated five times and the remaining tacky solid substance was dried under reduced pressure. An amount of 18.2 grams (3,7,11)-trimethyl-dodeca-2,6,10-trien-1-yl)triphenylphosphonium chloride (E/Z isomer mixture) was obtained. The yield was 87 percent of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:19][N+:16]2[CH:17]=[CH:18][N:14]([N:13]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n(N)cc[n+]2N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: COc1ccc(-c2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
131 mg of 4-(dimethylamino)benzaldehyde are added to a solution of 90 mg of 1,3-diamino-2-(4-methoxyphenyl) imidazolium chloride in 2 ml of glacial acetic acid. After stirring at room temperature for 48 hours, the dark yellow solution is evaporated. The residue is placed on a column loaded with 8 g of silica gel, whereupon the product is eluted with dichloromethane/ethanol (9:1) and recrystallized from ethanol/ether. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)imidazolium chloride of melting point 250°.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:40]([NH:42][C@H:43]([C:45](O)=[O:46])[CH3:44])=[O:41])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:31][CH:30]=3)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[NH2:55][CH2:56][C:57]1[C:70]([O:71][CH3:72])=[CH:69][CH:68]=[C:67]2[C:58]=1[O:59][C:60]1[C:61]([CH2:77][C:78]([O:80][CH2:81][C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)=[O:79])=[C:62]([O:75][CH3:76])[CH:63]=[CH:64][C:65]=1[C:66]2([CH3:74])[CH3:73].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:76][O:75][C:62]1[CH:63]=[CH:64][C:65]2[C:66]([CH3:74])([CH3:73])[C:67]3[C:58]([O:59][C:60]=2[C:61]=1[CH2:77][C:78]([O:80][CH2:81][C:82]1[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1)=[O:79])=[C:57]([CH2:56][NH:55][C:45](=[O:46])[C@H:43]([CH3:44])[NH:42][C:40](=[O:41])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:33][CH:34]=1)[NH:26][C:24](=[O:25])[C@H:19]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[C:70]([O:71][CH3:72])=[CH:69][CH:68]=3
Reactant: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C

Procedure:
A solution of 0.52 g (0.8 mmol) of N-(9H-fluoren-9-ylmethoxycarbonyl)-L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanine in 20 ml of dimethylformamide was cooled to 0° and treated with 0.45 g (0.8 mmol) of benzyl 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate trifluoroacetate and with 0.45 g (1.2 mmol) of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate. Thereafter, 0.31 g (2.4 mmol) of ethyldiisopropylamine was added, whereupon the reaction mixture obtained was warmed from 0° to room temperature within 3 hours and concentrated. The residue remaining was taken up in chloroform, whereupon the solution obtained was washed with water and dried over magnesium sulphate. After chromatography over silica gel (chloroform) 0.77 g of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(N-(9H-fluoren-9-ylmethoxycarbonyl)-L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate of m.p. 218°-220° was obtained; IR 1728, 1662, 1606, 1503, 1492 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>C(Cl)Cl>[CH3:10][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[C:7]([S:12]([Cl:11])(=[O:14])=[O:13])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1

Procedure:
A solution of 3,5-dimethylanisole (102.5 g, 753 mmol) in DCM (1000 ml) was cooled to 0° C. A solution of chlorosulfonic acid (251 ml, 3763 mmol) in DCM (250 ml) was added dropwise to this solution. After a reaction time of 10 min, the reaction solution was added to an ice bath (1000 ml), and the phases were separated and extracted again with DCM (250 ml). The combined organic phases were washed with water (1000 ml) and saturated sodium chloride solution (1000 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel (heptane/DCM 5:1). Yield: 63.5 g, 36%
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:9]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN([C@@H]2CCCC[C@H]2O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN([C@@H]2CCCC[C@H]2OCc2ccccc2)C1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of tert-butyl [(3R)-1-(trans-2-hydroxycyclohexyl)pyrrolidin-3-yl]carbamate (0.70 g, 2.46 mmol) and 60% NaH (0.108 g, 2.71 mmol) in DMF (5 mL) at 0° C. was added benzyl bromide (0.79 mL, 2.71 mmol). After being stirred overnight under N2, water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to 10% MeOH/EtOAc) to give 0.60 g of the title compound. MS (EI) calcd: (M+H)+=375.3. Found: 375.4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][C:14](=[O:16])[CH:13]=[CH:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(N(CC)CC)C.[Pd]>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=COC(COCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CCOC(COCc2ccccc2)C1
Yield: 56.8 %

Procedure:
A mixture of (RS)-2-benzyloxymethyl-2,3-dihydro-4H-pyran-4-one (0.82 g, J. Org. Chem., 44, 811 (1979)) in ethanol (15 ml) containing 10% Pd-C (0.089 g) and triethylamine (10 drops) was hydrogenated until NMR spectroscopy indicated almost complete reaction. The solution was evaporated and the residue purified by silica-gel MPLC [25% EtOAc/hexanes] and then bulb-to-bulb distillation [220° C./2 mmHg] to give the title ketone (0.47 g, 56%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH2:16]([S:24](Cl)(=[O:26])=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(#N)C>[CH2:16]([S:24]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)(=[O:26])=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCS(=O)(=O)ON=C(C#N)c1ccc(OC)c(OC)c1

Procedure:
As described under 1.2, 10.3 g (0.05 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 11.7 g (0.055 mol) of 1-octanesulfonyl chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/hexane, 19.1 g (87%) of α-(n-octylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of beige crystals having a melting point of 72-75° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 349 nm (ε=11330) that extends to 435 nm. Elemental analysis: C18H26N2O5S (382.48)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:18]([S:19][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(Br)cnc1OC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(SCc2ccccc2)cnc1OC
Temperature: 120 °C
Yield: 105.7 %

Procedure:
To a solution of 5-bromo-2,3-dimethoxypyridine (1.2 g, 5.50 mmol) in toluene (18 ml) was added phenylmethanethiol (0.71 ml, 6.05 mmol), N-ethyl-N-isopropylpropan-2-amine (2.00 ml, 12.1 mmol), Pd2(dba)3 (0.20 g, 0.22 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.26 g, 0.44 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was irradiated in the microwave with heating to 120° C. for 1 hour before being filtered through a pad of celite and washed with ethyl acetate (25 ml). The filtrate was concentrated to give an orange oil which was purified by column chromatography (SiO2; 0-15% ethyl acetate in petrol) gave 5-(benzylsulfanyl)-2,3-dimethoxypyridine as an orange oil (1.52 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([O:22]COC)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].C(OCC)(=O)C>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[C:14]([OH:22])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:26]([F:27])([F:28])[F:29]
Reactant: COCOc1cc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(O)cc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(3-methoxymethoxy-5-trifluoromethyl-phenyl)-urea (100 mg, 0.25 mmol) from above was dissolved in a 1:1 solution of 3N HCl/ethyl acetate (20 mL) and stirred vigorously at room temperature for 16 h. Additional ethyl acetate was then added (50 mL) and the mixture was washed with water (2×50 mL), brine (50 mL), dried over Na2SO4, and concentrated. The resulting residue was purified using silica gel flash chromatography eluting with a 3:1 hexane/ethyl acetate solution. Similar fractions were pooled and concentrated to the title compound (72 mg, 72%) as an off-white solid. 1H NMR (CD3OD) δ 7.97 (d, J=2 Hz, 1 H), 7.64 (dd, J=2 Hz, J=8 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.22 (s, 1H), 7.21 (s, 1H), 6.75 (s, 1H); Electrospray MS (MH+) m/z 399.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12.[O:16]([CH2:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[O:16]([CH2:23][C:24]([NH:1][C@@H:2]1[C:14](=[O:15])[N:4]2[CH:5]([C:11]([OH:13])=[O:12])[C@:6]([CH:9]=[CH2:10])([CH3:8])[S:7][C@H:3]12)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: C=C[C@@]1(C)S[C@@H]2[C@H](N)C(=O)N2C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C[C@@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O

Procedure:
6β-Amino-2α-vinyl-2β-methylpenam-3-carboxylic acid is acylated in acetone-water with phenoxyacetyl chloride in the presence of sodium carbonate to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[Cl-:33].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S+:11]([C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(S(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CC(C)(C)c1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Product: [Cl-]

Procedure:
The end product was synthesized as in Synthesis Example 2 except that bis(4-tert-butylphenyl)sulfoxide was used instead of the phenyl sulfoxide and 4-tert-butylchlorobenzene was used instead of the chlorobenzene.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[Cl:39])[C:29]([C:40]4C=CC=CC=4)=[C:28]([OH:46])[C:27]3=[O:47])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO.O>[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[Cl:39])[C:29]([CH3:40])=[C:28]([O:46][CH3:3])[C:27]3=[O:47])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2c(F)ccc(F)c2Cl)N1c1ccc2nc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1=C(C)C(c2c(F)ccc(F)c2Cl)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq) ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(2-chloro-3,6-difluorophenyl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (0.103 g, 0.25 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.013 g (13.3%); MS m/z: 390.2 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.78, 1.81 (2s, 3H), 3.94, 3.95 (2s, 3H), 6.34-6.35 (m, 1H), 7.11-7.17 (m, 1H), 7.25-7.29 (m, 1H), 7.35-7.40 (m, 1H), 7.52-7.54 (m, 1H), 7.67 (s, 1H), 8.35 (s, 1H); HPLC (METHOD [A]): rt 12.59 min (95%)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@H:17]([O:34][C:35]([CH2:39][F:40])([CH3:38])[CH2:36][F:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@H:17]([O:34][C:35]([CH2:36][F:37])([CH3:38])[CH2:39][F:40])[CH2:16]1)=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OC(C)(CF)CF)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(O)cc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@H](OC(C)(CF)CF)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Add acetic anhydride (2.13 mmoles; 201.52 μL) to a solution of (2R,5R)-5-[(1S,2S)-2-amino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-2-(2-fluoro-1-fluoromethyl-1-methyl-ethoxy)-morpholine-4-carboxylic acid tert-butyl ester (2.03 mmoles; 1.00 g) and triethylamine (2.23 mmoles; 311.29 μL) in 10 mL dichloromethane at 0° C. (ice bath) and stir the mixture at 0° C. for 1 h. Concentrate under reduced pressure and subject residue to silica gel chromatography eluting with 40:60 to 0:100 hexane/ethyl acetate gradient to give the desired compound as white solid (950.00 mg, 87.53%).
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]([N:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Cl:41])[CH:35]=2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23](CS(C)(=O)=O)=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[CH:9]=[CH:10][CH:11]=1)=O)C=C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[Cl:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[F:40])[CH2:33][N:12]1[C:13](=[O:32])[C:14]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:16][S:17]([CH3:18])(=[O:31])=[O:30])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)=[C:5]([OH:4])[C:7]2=[CH:11][CH:10]=[CH:9][N:8]12
Reactant: C=CCOC(=O)c1cccn1N(Cc1ccc(F)c(Cl)c1)C(=O)CC1=NS(=O)(=O)c2cc(CS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(Cc3ccc(F)c(Cl)c3)c1=O)N2
Temperature: 60 °C
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a solution of 1-{(3-chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylmethyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-1H-pyrrole-2-carboxylic acid allyl ester (Example 17i, 304.5 mg, 0.488 mmol) in absolute ethanol (5 mL) was added a 21% solution of sodium ethoxide in ethanol (1.1 mL, 2.95 mmol). After stirring at 60° C. for 12 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution upon which a precipitate formed. The solid was collected by vacuum filtration to afford the desired product, N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (88.5 mg, 0.156 mmol, 32% yield) as an off-white solid. The filtrate was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by HPLC purification (Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 25%-100% in 12 min 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) to afford more of the desired product, N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (18.4 mg, 0.033 mmol, 7% yield; total 39% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.06 (3H, s), 5.61 (2H, s), 6.57 (1H, s), 6.98 (1H, s), 7.37 (2H, d, J=7.6 Hz), 7.52 (1H, dd, J1=8.5 Hz, J2=2.4 Hz), 7.59-7.68 (4H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C22H17ClFN5O6S2 565.03. found 566.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](I)[CH3:24].N1CCOCC1>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:23][CH3:24])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Reactant: CCI
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCn1c(=O)n(C)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 90 h
Yield: 69.8 %

Procedure:
To a solution of 8-chloro-1-methyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (58 mg, 0.54 mmol), after 10 minutes stirring ethyl iodide (0.043 ml, 0.54 mmol) was added and the reaction mixture stirred at room temperature under nitrogen for 90 hours. Pd(PPh3)4 (73 mg, 0.063 mmol) was then added and the reaction vessel evacuated and flushed with nitrogen (x3), morpholine (0.37 ml, 4.3 mmol) was added and stirring at room temperature under nitrogen continued for 4 hours. The reaction mixtue was diluted with EtOAc (25 ml) and washed with 2M HCl aq. (25 ml). The organic extract was dried (MgSO4) filtered and evaporated. Purification by aminopropyl SPE (5 g) loading the compound and washing with MeOH before eluting the product with 5% AcOH/MeOH afforded the title compound as a white solid (67 mg, 70%). NMR; dH (400 MHz, d6-DMSO) 1.20 (t, 3H, J=7 Hz), 3.22 (s, 3H), 3.97(q, 2H, J=7 Hz), 14.46 (1H, br s); m/z 227.2[M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]([C:15]2[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=[N:17][C:16]=2[CH3:39])[OH:14])=[CH:5][CH:4]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:40][N:2]([CH3:1])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:15]2[N:19]=[CH:18][NH:17][C:16]=2[CH3:39])=[CH:5][CH:4]=1.[CH3:1][N:2]([CH3:40])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]([C:15]2[N:19]=[CH:18][NH:17][C:16]=2[CH3:39])[OH:14])=[CH:5][CH:4]=1
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(O)c1ccc(N(C)C)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]cnc1C(O)c1ccc(N(C)C)c2ccccc12
Product: Cc1[nH]cnc1Cc1ccc(N(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %
Yield: 25 %

Procedure:
A solution of (4) (3.35 g, 6.40 mmol) in TFA (30 mL) was added triethylsilane (6 mL, 38.4 mmol). The reaction mixture was stirred at room temperature overnight. TFA was removed under vacuum. The residue was basified with 2 M sodium hydroxide to pH>7. The aqueous layer was extracted three times with chloroform/isopropanol (3:1200 mL). The pooled organic layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 2 to 5% saturated ammonia methanol in dichloromethane to give N,N-dimethyl-4-((5-methyl-1H-imidazol-4-yl)methyl)naphthalen-1-amine (5) (0.55 g, 2.07 mmol, 32% yield), and (4-(dimethylamino)naphthalen-1-yl)(5-methyl-1H-imidazol-4-yl)methanol (6) (0.45 g, 1.60 mmol, 25% yield).