Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC.[CH3:20][C:21]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[C:22](=[O:24])[CH3:23].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:18]([O:17][CH:10]([O:14][CH2:15][CH3:16])[CH2:23][C:22](=[O:24])[C:21]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:20])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)OC(C)(C)C(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(CC(=O)C(C)(C)OC(C)=O)OCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Boron trifluoride etherate (17.03 g, 120.0 mmol) was added drop-wise over 15 min to a cooled (−40° C.) solution of triethyl orthoformate (14.82 g, 100.0 mmol) in dichloromethane (50 ml). Stirring was continued for 10 min then the solution was transferred to an ice-water bath and stirred at 0° C. for 20 min. The mixture was cooled to −78° C., and acetic acid 1,1-dimethyl-2-oxopropyl ester (7.21 g, 50.0 mmol) added followed by drop-wise addition of N,N-diisopropylethylamine (19.39 g, 150.0 mmol) over 15 min. Stirring was continued for 1 h then the solution was poured onto a vigorously stirred mixture of saturated sodium hydrogencarbonate solution (500 ml) and dichloromethane (200 ml). The organic phase was separated, washed with ice-cold 1N sulfuric acid solution (2×500 ml) and ice-cold water (2×500 ml), dried over anhydrous sodium sulfate solution and evaporated to give acetic acid 4,4-diethoxy-1,1-dimethyl-2-oxobutyl ester (12.32 g, 100%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][CH2:3][C:2]2([CH3:13])[CH3:1]
Reactant: Cc1ccc2c(c1)C(C)(C)CCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCOc2ccc(CBr)cc21

Procedure:
A mixture of 5.0 g (28.4 mmole) of 4,4,6-trimethylchroman, 5.55 g of purified N-bromosuccinimide and 200 ml of carbon tetrachloride was heated under reflux for 12 hours. The succinimide was removed by filtration and the solvent was removed by evaporation in vacuo to give the title compound as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([N+:82]([O-])=O)[C:46]=1[O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C:55](=[O:81])/[CH:56]=[CH:57]/[C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65](=[O:80])[C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH2:74][CH2:75][C:76]([F:79])([F:78])[F:77])=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O.C(OCC)(=O)C>CN(C)C=O.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([NH2:82])[C:46]=1[O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C:55](=[O:81])/[CH:56]=[CH:57]/[C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65](=[O:80])[C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH2:74][CH2:75][C:76]([F:77])([F:78])[F:79])=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:40])([F:39])[F:41])=[CH:30][CH:29]=2)=[CH:24][CH:25]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])c(OCCCCCCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)cc(N)c1OCCCCCCOC(=O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Yield: 0.1 %

Procedure:
7.70 g (6.5 mol) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-dinitro-4-[6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl) oxy]phenyl}prop-2-enoyl)oxy]}hexyloxy]benzoate are dissolved in a mixture of 90 ml of N,N-dimethylformamide and 7 ml water. 10.6 g (39.2 mmol) ferric chloride hexahydrate are added. 4.27 g (65.36 mmol) Zinc powder are added portionwise within 40 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using toluene:ethyl acetate 2:1 as eluant and crystallization form methanol:ethyl acetate mixture to yield 4.92 g 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-Diamino-4-[6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyloxy]benzoate as colorless crystals.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[C:8]1[C:9]([C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1>Cl>[CH2:1]([O:6][C:8]1[C:9]([C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OC1(c2nccnc2Cl)CN2CCC1CC2
Reactant: CCCCCO
Agent: Cl
Product: CCCCCOc1nccnc1C1(O)CN2CCC1CC2
Temperature: 70 °C

Procedure:
To a solution of 30 ml of pentanol that had reacted with 0.5 g of Na (0.022 mol) was added 1.7 g of (7) (0.0071 mol). The reaction was heated to 70° C. for 2 h, the reaction cooled to ambient temperature, and 30 ml of 1 N HCl was added. The excess pentanol was azeotroped off with water and the residue made basic with 5 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% N and then with 10% ethanol-1% NH4OH-CHCl3 to give 1.68 g of 3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol. NMR ppm (CDCl3) 0.97 (3H, t), 1.2 (1H, m), 1.45 (6H, m), 1.87 (2H, m), 2.3 (1H, m), 2.4 (1H, t), 2.8 (1H, m), 2.93 (3H, m), 3.1 (1H, m), 3.98 (1H, s), 4.28 (1H, d), 4.42 (2H, m), 8.01 (1H, d), 8.11 (1H, d). A solution of 1.48 g of this alcohol (0.0051 mol) in 50 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 5 ml of CH2Cl2 was added dropwise. The cooling was removed, the reaction stirred 1.5 h and then heated to reflux for 45 min. After cooling to ambient temperature, ice-water was added to the reaction and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol- 0.5% N4OH-CHCl3 to give 1.27 g of 3-chloro-3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octane. NMR ppm (CDCl3) 0.99 (3H, t), 1.35-1.8 (7H, m), 1.9 (2H, m) 2.37 (1H, m), 2.6-2.82 (2H, m), 3.0 (1H, t), 3.15 (2H, m), 3.6-4.1 (2H, m), 4.42 (2H, t), 8.06 (2H, m). A mixture of 1.05 g of this chloride (0.0034 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated 1 h at 60 psi of H2. The catalyst was filtered off, 25 ml of isopropanolic HCl was added, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 0.28 g of (25), mp 166°-167° C. NMR ppm (CDCl3) 0.95 (3H, t), 1.41 (4H, m), 1.57-1.9 (5H, m), 2.13 (2H, m), 2.45 (1H, m), 3.12 (1H, m), 3.3-4.46 (3H, m), 3.55 (1H, m), 3.7 (1H, m), 4.3 (1H, q), 4.37 (2H, t), 8.03 (1H, d), 8.1 (1H, d). Anal. C16H25N3O-HCl requires C: 61.62; H: 8.40; N: 13.47%. Found C: 61.39; H: 8.07; N: 13.48%.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][C:4]#[C:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:20]([O:22][CH3:23])=[O:21])[C:13]2=[O:16])=[CH:8][CH:7]=1.CO.C(OCC)(=O)C>C(O)C.[Pd]>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:20]([O:22][CH3:23])=[O:21])[C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(C#CCN(C)C)cc3c2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(CCCN(C)C)cc3c2=O)c1

Procedure:
Methyl 3-[7-[3-(dimethylamino)prop-1-yn-1-yl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate (192 mg) and 10% Pd/C (20 mg) were stirred in a mixture of ethanol (2 ml)/methanol (4 ml)/ethyl acetate (1 ml) under an atmosphere of hydrogen at room temperature for 2 hours. The catalyst was removed by filtration through a microfibre filter and the filtrate was concentrated to yield an oil. The oil was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to yield methyl 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate as a yellow oil that turned to a pale yellow solid on standing (155 mg); NMR Spectrum: (DMSOd6) 1.76 (m, 2H), 2.14 (s, 6H), 2.15 (s, 3H), 2.23 (t, 2H), 2.76 (t, 2H), 3.87 (s, 3H), 6.72 (d, 1H), 7.30 (d, 1H), 7.59 (d, 1H), 7.67 (m, 2H), 7.83 (s, 1H), 7.98 (d, 1H), 8.07 (s, 1H); Mass Spectrum: M+H+ 379.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:48]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.34 ml, 7.69 mmol), 3-aminopyridine (0.43 g, 4.61 mmol) and HATU (2.19 g, 5.77 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 1.25 g, 3.84 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours. The solid was then filtered and washed with ethyl acetate to yield the title compound as a white solid. 650 mg.
Reaction SMILES: [NH3:1].F[C:3]1[C:10]([F:11])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N:12](S(C)(=O)=O)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:4]=1>O1CCCC1>[NH2:1][C:3]1[C:10]([F:11])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:4]=1
Reactant: CS(=O)(=O)N(c1cc(F)c(F)cc1C#N)S(C)(=O)=O
Reactant: N
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(N)c(F)cc1C#N
Temperature: 150 °C
Yield: 34 %

Procedure:
In a 100 ml autoclave, 2 ml of ammonia are condensed and 2.0 g (6.4 mmol) of 4,5-difluoro-2-(bis-methanesulphonyl-amino)-benzonitrile and 40 ml of tetrahydrofuran are added. The reaction mixture is then heated in the closed autoclave at 150° C. for 15 hours. After cooling, the mixture is filtered and the filtrate is concentrated under water pump vacuum. Washing with 2N hydrochloric acid and with water gives 0.50 g (34% of theory) of N-(5-amino-2-cyano-4-fluoro-phenyl)-methanesulphonamide of melting point 235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].Cl[C:44]1C=CC(Cl)=CC=1S(Cl)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:44])[C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5c(C)cccc5Cl)c4)cc23)CC1
Yield: 30 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting 2-chloro-6-methylbenzenesulfonyl chloride (86 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 17.9 mg the title compound (30%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]#[C:5][C:6]1[C:27]([O:28][CH3:29])=[CH:26][C:9]2[C:10]([CH3:25])([CH3:24])[C:11]3[NH:12][C:13]4[C:18]([C:19]=3[C:20](=[O:21])[C:8]=2[CH:7]=1)=[CH:17][CH:16]=[C:15]([C:22]#[N:23])[CH:14]=4.Cl>CO.C1COCC1.[OH-].[K+]>[C:22]([C:15]1[CH:14]=[C:13]2[C:18]([C:19]3[C:20](=[O:21])[C:8]4[CH:7]=[C:6]([C:5]#[C:4][C:3]([OH:30])=[O:2])[C:27]([O:28][CH3:29])=[CH:26][C:9]=4[C:10]([CH3:24])([CH3:25])[C:11]=3[NH:12]2)=[CH:17][CH:16]=1)#[N:23]
Reactant: COC(=O)C#Cc1cc2c(cc1OC)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1C#CC(=O)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-propynoic acid methyl ester (Compound E6-1, 15.2 mg, 0.038 mmol) was dissolved in a mixture solvent of methanol (1.5 mL) and THF (0.5 mL), added with 2 N aqueous solution of potassium hydroxide (5 drops), and then stirred at room temperature overnight. 0.5 N Hydrochloric acid was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solids obtained after filtration and concentration under reduced pressure were washed with dichloromethane and purified by HPLC to obtain the title compound (white solid, 9.6 mg, 66%).
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([OH:24])=O)[N:16]=1)=[O:13].[NH2:33][CH:34]1[C:51](=[O:52])[N:36]2[C:37]([C:48]([OH:50])=[O:49])=[C:38]([CH2:41][S:42][C:43]3[S:44][CH:45]=[N:46][N:47]=3)[CH2:39][S:40][C@H:35]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl.CC(C)=O.C(OCC)(=O)C.CN(C)C=O>[CH:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([NH:33][CH:34]2[C:51](=[O:52])[N:36]3[C:37]([C:48]([OH:50])=[O:49])=[C:38]([CH2:41][S:42][C:43]4[S:44][CH:45]=[N:46][N:47]=4)[CH2:39][S:40][C@H:35]23)=[O:24])[N:16]=1)=[O:13]
Reactant: O=CNc1ccnc(C(=NOc2ccccc2)C(=O)O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=CNc1ccnc(C(=NOc2ccccc2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)n1
Yield: 69.3 %

Procedure:
Methylene chloride (15 ml) was added to a Vilsmeier reagent, which was prepared by phosphoryl chloride (0.75 g) and N,N-dimethylformamide (0.75 ml) in a conventional manner. To this mixture was added 2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer) (1.0 g) at -20° C., followed by stirring at -15° to -13° C. for half an hour. To this solution was added a solution of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (1.27 g) and trimethylsilylacetamide (4.6 g) in methylene chloride (14 ml) at -20° C. with stirring, and the stirring was continued at -15° to -13° C. for half an hour and at ambient temperature for additional half an hour. The reaction mixture was evaporated to give a residue, to which ethyl acetate and then an aqueous solution of sodium bicarbonate were added. To the separated aqueous solution was added ethyl acetate and then adjusted to pH 1 to 2 with hydrochloric acid. After addition of a small amount of acetone, the organic layer was separated, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated. The residue was pulverized with diethyl ether to give 7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=O.[NH2:19][NH2:20]>C(O)C.C(OCC)(=O)C.O1CCCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:10]2[C:11](=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)[NH:20][N:19]=1
Reactant: NN
Reactant: CSc1ncc(C(=O)c2ccccc2Cl)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CSc1ncc2c(-c3ccccc3Cl)n[nH]c2n1

Procedure:
To a solution of (2-chlorophenyl)-(4-chloro-2-methylsulfanylpyrimidin-5-yl)-methanone (5.3 g, 17.72 mmol) in ethanol (25 mL) was added anhydrous hydrazine (1.12 ml, 2 eq) dropwise with stirring. The reaction was then stirred for 20 minutes, after which it was cooled in an ice bath and the precipitated solid was removed by filtration. The solid was rinsed with cold ethanol. The filtrate was concentrated to provide a crude oil, which was diluted with ethyl acetate (80 mL), tetrahydrofuran (10 mL), methanol (5 mL), and water (80 mL). This mixture was partitioned and the layers separated. The organic layer was collected and dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow powder (2.81 g, (M+H)+=277).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)(=[O:14])=[O:13])([O-])=O.[Sn](Cl)Cl>Cl>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)(=[O:14])=[O:13]
Reactant: COc1ccc(S(=O)(=O)Nc2cccc3ccc(C)nc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: COc1ccc(S(=O)(=O)Nc2cccc3ccc(C)nc23)c(N)c1
Yield: 72.8 %

Procedure:
In the similar fashion using route 1 general procedure 4, 2-nitro-4-methoxy-N-(2-methyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 150) (550 mg, 1.4 mmol), tin (II) chloride (838 mg, 4.4 mmol) and 6N HCl (2 drops) gave the title compound (350 mg, 70%).
Reaction SMILES: [I:1]I.[F:3][C:4]([F:35])([F:34])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C@H:19]([CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH2:20]O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C1C=CC=CC=1>[I:1][CH2:20][C@H:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][C:4]([F:35])([F:34])[F:3])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)[Si](OC[C@H](CO)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)(C(C)C)C(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)[Si](OC[C@H](CI)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of the benzyl ether 80 (10.79 g, 0.019 mol) and 5% Pd—C (500 mg) in 1:1 EtOAc/EtOH (250 mL) was hydrogenated at 60 psi for 4 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure to give (2S)-2-{[4′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl]oxy}-3-[(triisopropylsilyl)oxy]-1-propanol (81) as a viscous oil, sufficiently pure for use in the next step. Iodine (6.03 g, 0.024 mol) was added in portions at 20° C. to a vigorously stirred solution of the crude alcohol 81, triphenylphosphine (6.23 g, 0.024 mol) and imidazole (2.49 g, 0.036 mol) in benzene (100 mL) and stirring was continued for 1 h. After dilution with EtOAc the mixture was washed with water, 2N Na2SO3 and water again. The extract was evaporated and chromatographed on silica gel, eluting with EtOAc/petroleum ether (1:19), to give 4-[((1R)-2-iodo-1-{[(triisopropylsilyl)oxy]methyl}ethyl)oxy]-4′-(trifluoromethoxy)-1,1′-biphenyl (82) (9.08 g, 81% overall) as a colourless oil; 1H NMR (CDCl3) δ 7.54 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.26 (br d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 4.31-4.25 (m, 1H), 4.03 (dd, J=10.4, 4.8 Hz, 1H), 3.93 (dd, J=10.4, 5.6 Hz, 1H), 3.55 (dd, J=10.5, 5.6 Hz, 1H), 3.45 (dd, J=10.5, 4.8 Hz, 1H), 1.15-1.06 (m, 21H). APCI MS m/z 595 [M+H]+.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([NH:14][CH:15]=O)=[C:9]([OH:17])[N:8]=1>>[NH:8]1[C:9](=[O:17])[C:10]2[NH:14][CH:15]=[N:13][C:11]=2[N:12]=[C:7]1[NH2:6]
Reactant: Nc1nc(N)c(NC=O)c(O)n1
Agent: O=S(=O)([O-])[O-]
Product: Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
In the process based on TAHP sulfate described above, 2,4-diamino-5-formylamino-6-hydroxypyrimidine (referred to as DAFHP below) is passed through as an intermediate, which is reacted in situ to produce guanine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: B
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
30.0 g (0.128 mol) of 3-(4-bromophenyl)propionic acid are initially introduced in 300 ml of THF, and 257 ml (0.257 mol) of a 1 M solution of boron hydride in THF are added dropwise with ice cooling. The batch is left to stir overnight at room temp., carefully hydrolysed with cooling, and extracted three times with MTB ether. The combined org. phases are washed with sat. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with MTB ether, giving 3-(4-bromophenyl)propan-1-ol, which is employed in the next step without further purification.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc(C=O)cc1
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Product: CCCc1c(OC)cc(C=Cc2ccc(OC)cc2)cc1OC
Yield: 63 %

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 4-anisaldehyde in 63% yield as the same procedure as described in Example 5(b). 1H NMR (CDCl3, ppm): δ 1.31 (d, J=7.1 Hz, 6H), 3.51-3.74 (m, 1H), 3.86 (s, 3H), 3.91 (s, 6H), 6.71 (s, 2H), 6.84-7.09 (m, 4H), 7.39-7.60 (m, 2H).