Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:23][CH2:24][CH3:25].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH2:24][CH3:25]
Reactant: CCOc1c(/C(C)=C(/F)CO)cc2c(c1Cl)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-144, 0.18 g, 0.49 mmol), tetrapropylammonium perruthenate (25 mg, 0.071 mmol) and 4-methylmorpholine N-oxide (115 mg, 0.98 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.O.[CH3:17][O:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:17][O:18][C:19]1[C:24]([C:2]2[C:3]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncccc1-c1nccnc1Oc1ccc(N)cc1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added 4-(3-chloropyrazin-2-yloxy)aniline (1.0591 g, 4.78 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine hydrate, trans-dichlorobis(triphenylphosphine) palladium (II) (0.268 g, 0.382 mmol), and sodium carbonate (2.53 g, 23.89 mmol) in DME (7.65 mL) and water (1.911 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 100° C. for 15 min. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 4(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)aniline. MS (ESI, pos. ion) m/z:295.2.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][C:37](=O)[CH3:38])=O)[CH3:32])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:38][C:37]1[S:10][C:33]([C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:32])=[N:35][CH:36]=1
Reactant: CC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1cnc([C@@H](C)NC(=O)OC(C)(C)C)s1
Yield: 33.5 %

Procedure:
Lawesson's Reagent (14 g, 35 mmol) was added to a solution of N2-(tert-butoxycarbonyl)-N-(2-oxopropyl)-D-alaninamide (8.5 g, 34.5 mmol) in THF (300 ml), and the resulting mixture was refluxed for 6 h. After concentration, the residue was purified by column, and 2.8 g of tert-butyl [(1R)-1-(5-methyl-1,3-thiazol-2-yl)ethyl]carbamate was obtained as solid (35%). 1H-NMR CDCl3 δ 7.31 (s, 1H), 5.24 (br, 1H), 5.00 (m, 1H), 2.42 (s, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.44 (s, 9H) ES-MS [M+1]+: 243.14.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:13])=[O:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([C:17]1[N:18]=[C:19]([C:22]([NH:1][C:2]2[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=2[C:11](=[O:12])[CH3:13])=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: CC(C)c1csc(C(=O)Cl)n1
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (18.6 g, 104 mmol) in dioxane (50 mL) was added under nitrogen to a suspension of 4-isopropylthiazole-2-carbonyl chloride in dioxane (250 mL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution of NaHCO3 and AcOEt, organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90%) of the title product 35.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][O:9][C:8]1=[O:13])([O-])=O.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][O:9][C:8]1=[O:13]
Reactant: O=C1OCCCN1Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1CN1CCCOC1=O
Temperature: 25 °C

Procedure:
3-(2-Nitrobenzyl)-[1,3]-oxazinan-2-one (0.24 g, 1.02 mmol), iron powder (0.28 g, 5.02 mmol), ammonium chloride (0.03 g, 0.56 mmol) were suspended in ethanol (10 ml) and water (5 ml) and heated to reflux for one hour. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and 3-(2-aminobenzyl)-[1,3]-oxazinan-2-one was obtained by evaporating the solvent under reduced pressure (0.20 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:18][CH2:17]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)CCO)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)CCO)CC1

Procedure:
Following general procedure II, 1-[6-chloro-4-(4-{[(2-hydroxyethyl)(methyl)amino]-methyl}cyclohexylamino)-1,5-naphthyridin-3-yl]ethanone (30 mg, 0.076 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31 mg, 0.11 mmol) followed by formation of the dihydrochloride salt to afford the desired product (32 mg, 73%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J=11.5 Hz, 1H), 5.74-5.71 (m, 1H), 3.90 (t, J=5.1 Hz, 2H), 3.45-3.32 (m, 1H), 3.30-3.26 (m, 2H), 3.07-3.04 (m, 1H), 2.97 (s, 3H), 2.76 (s, 3H), 2.45 (s, 2H), 2.17-2.02 (m, 3H), 1.70-1.62 (m, 2H), 1.48-1.36 (m, 2H); ESI MS m/z 501 [M+H]+; HPLC 98.2% (AUC), tR=9.54 min.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[C:22]([S:24]([N:27]([CH2:29][CH2:30][CH2:31][CH3:32])[CH3:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[CH3:33])(C)(C)C>C(OCC)C.CCCCC>[CH2:29]([N:27]([CH3:28])[S:24]([C:22]1[CH:21]=[CH:20][C:19]([CH3:33])=[C:18]([C:17]#[C:16][C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:34])=[O:5])[CH:23]=1)(=[O:25])=[O:26])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN(C)S(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Solvent: CCCCC
Solvent: CCOCC
Product: CCCCN(C)S(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1
Yield: 96 %

Procedure:
Following the general method as outlined in Example 15, starting from tert-butyl{2-[(5-{[butyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 161), the title compound was obtained as a beige solid in 96% yield after trituration in diethyl ether/pentane.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH3:15]>ClCCl>[Br:9][C:10]1[S:11][C:12]([C:1](=[O:3])[CH3:2])=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccsc1Br
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(Br)s1
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
Acetyl chloride (7.09 g) is added to a suspension of AlCl3 (11.53 g) in dichloromethane (310 ml) at 0° C. After 45 minutes at 0° C., 2-bromo-3-methylthiophene (5.0 g) is added dropwise. After 1 hour at 0° C., the reaction is quenched by added water (100 ml). The mixture is extracted three times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on silica gel (180 g) eluting with a mixture of ethyl acetate and heptane (1:6) to yield 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (3.5 g) as a brown solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:21]([C@@H:24]3[CH2:29][C@@H:28]4[C@@H:26]([CH2:27]4)[N:25]3C(OC(C)(C)C)=O)[NH:22][CH:23]=1)[CH:13]=[CH:12]2>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:21]([C@@H:24]3[CH2:29][C@@H:28]4[C@@H:26]([CH2:27]4)[NH:25]3)[NH:22][CH:23]=1)[CH:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc3cc(Br)ccc3c2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Brc1ccc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 166.3 %

Procedure:
TFA (1.028 mL, 13.34 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 120) (606 mg, 1.334 mmol) in DCE (20 mL) and reaction was stirred at rt for 2 h. Then additional TFA (1 mL) was added and the reaction was stirred at rt for 4 h. The reaction was concentrated to dryness and the crude brown oil was dissolved into diethyl ether and concentrated under vacuum (2×) to yield a TFA salt of (1R,3S,5R)-3-(4-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (786 mg) as a yellow solid. The material was used without further purification. LC-MS retention time 2.558 min; m/z 352.03, 354.05 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 10.55 (br. s., 1H), 8.02 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.8 Hz. 1H), 7.59 (dd, J=8.8, 2.0 Hz, 1H), 7.52 (dd, J=8.7, 1.6 Hz, 1H), 7.44 (s, 1H), 5.10 (dd, J=11.8, 7.3 Hz, 1H), 3.49-3.54 (m, 1H), 2.94 (td, J=12.7, 4.6 Hz, 1H), 2.68 (dd, J=13.2, 7.2 Hz, 1H), 2.06-2.14 (m, 1H), 1.20-1.26 (m, 1H), 1.00-1.09 (m, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)[CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:8]2[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=2)[CH2:7][CH2:6]1
Reactant: Nc1nnc(C2CC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclopropyl-2-amino-1,3,4-thiadiazole (6 grams) in ethyl acetate (100 ml) was added to the reaction vessel, and the resulting mixture was stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was filtered to recover the desired product 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:39])=[CH:27][C:26]=1[Cl:46].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:46][C:26]1[CH:27]=[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)=[O:39])[C:29]2[O:33][CH2:32][O:31][C:30]=2[C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1c(Cl)cc(C#CCNC(=O)N2CCOCC2)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N4CCOCC4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 72.1 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]morpholine-4-carboxamide (220 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (272 mg, 72%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.47 (t, 2H), 2.50 (m, 4H), 3.55-3.62 (m, 8H), 3.94 (s, 3H), 4.14 (d, 2H), 4.20 (t, 2H), 6.15 (s, 2H), 7.10 (m, 2H), 7.20 (s, 1H), 7.82 (s, 1H), 8.34 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 639/641.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[N:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:19]3[N:20]=[N:21][CH:22]=[N:18]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: O=c1[nH]ccn1-c1ccc(-n2ncnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Yield: 10.7 %

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.34 g), 1-[4-(2H-2-tetrazolyl)-phenyl]-2(1H,3H)-imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to 1-methyl-2-pyrrolidone (100 ml), and the mixture was heated at 80° C. for 18 hours with stirring. The reaction solution was cooled, diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/acetone=1/1) to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 40; 0.494 g) as a colorless crystalline powder.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C([BH3-])#N.[Na+]>CO>[CH:31]1([N:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:10]4[NH:9][CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)=[CH:17][N:16]=3)[CH2:19][CH2:20]2)[CH2:33][CH2:32]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: c1ccc(-c2cnc(-c3ccc(N4CCNCC4)nc3)[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(-c2c[nH]c(-c3ccc(N4CCN(C5CC5)CC4)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
(Reference: Tetrahedron Lett. 1995, 36 (41), 7399) To a solution of 1-[5-(5-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine (99 mg, 0.32 mmol) in anhydrous methanol (5 ml) under nitrogen atmosphere was added 3A molecular sieves (50 mg). This solution was stirred for 5 min, then glacial acetic acid (0.19 ml, 200 mg, 3.3 mmol, 10 equiv), (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.32 ml, 281 mg, 1.62 mmol, 5 equiv), and sodium cyanoborohydride (81 mg, 1.29 mmol, 4.0 equiv) were added. The reaction was heated at reflux overnight, then cooled to room temperature. The mixture was filtered, then diluted with an aqueous solution of 1 N NaOH and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired product (74 mg, 66%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][CH3:19].[F-].[K+].[I-].[K+]>C(#N)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:7]=2[CH:13]=1
Reactant: O=C1COc2ccc(CO)cc2N1
Reactant: COCCCCl
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)COc2ccc(CO)cc21

Procedure:
A suspension of 1.79 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one, 2.20 ml of 1-chloro-3-methoxypropane, 10 g of KF on aluminium oxide and 0.033 g of potassium iodid in 150 ml of acetonitrile is stirred under reflux for 72 hours. The reaction mixture is cooled and clarified by filtration, and the filltrate is evaporated to dryness. The title compound is obtained from the residue by flash chromatography (SiO2 60 F). Rf (CH2Cl2/MeOH 9:1)=0.60; Rt =2.74.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].O>CN(C=O)C>[CH3:12][N:13]([CH3:17])[C:14](=[S:15])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC(=S)N(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 57.5 %

Procedure:
A solution of 4-bromo-3-methylphenol (8.15 g, 43.6 mmol) in DMF (250 mL) at RT was treated with a suspension of NaH (1.25 g, 52.3 mmol) in 10 mL of DMF. After 15 minutes the solution was cooled to 0° C. and dimethylthiocarbamoyl chloride (8.08 g, 65.4 mmol) was added. The reaction mixture was warmed up to 80° C. and stirred for 45 minutes. After cooling to RT, the mixture was poured into water (1 L). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil. The crude yellow oil material was purified by silica gel chromatography (5-50% EtOAc in hexanes) to afford 6.87 g of O-4-bromo-3-methylphenyl dimethylcarbamothioate as a clear, colorless oil. MS+=276.0 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([CH3:28])[C:24]=2[CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1coc2ccc(N)cc12
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2occ(C)c2c1
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (128 mg, 0.571 mmol) in dichloromethane (3 mL) was added pyridine (110 μL, 1.36 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-3-methyl-benzofuran (80 mg, 0.54 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a yellow solid (159 mg, 87%), single spot at Rf 0.65 (2:1 hexane:ethyl acetate). mp 119.5-120.1° C., HPLC purity 99% (tR 2.22 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.82 (1H, d, J=7.9 Hz), 7.54 (1H, d, J=7.9 Hz), 7.38 (1H s), 7.28-7.22 (2H, m), 7.15 (1H, t, J=8.0 Hz), 6.83 (1H, dd, J=8.7, 2.2 Hz), 6.56 (1H, s, N—H, 2.72 (3H, s), 2.15 (3H, s). LCMS: 334.07 (M−). FAB-MS (MH+, C16H14ClNO3S): calcd 335.0383, found 335.0383.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]([CH:10]=[O:11])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:7]1[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH:9][C:8]=1[CH:10]=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1ncc(C=O)[nH]1
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Butyl-3H-imidazole-4-carbaldehyde (30.0 g, 197 mmol) was dissolved in DMF (220 mL, 2.8 mol). NBS (36.8 g, 207 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated and taken up in EtOAc and water. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The mixture was purified by silica gel chromatography (0-50%
Reaction SMILES: ClC1C=CSC=1C[C@H]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])CC.CC(C)([O-])C.[K+].[F:28][C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[C:33](F)[CH:32]=[CH:31][N:30]=1>O1CCCC1>[F:28][C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[C:33]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH:32]=[CH:31][N:30]=1
Reactant: CC[C@H](Cc1sccc1Cl)NS(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])c1c(F)ccnc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccnc(F)c2[N+](=O)[O-])cc1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 129.3 %

Procedure:
A first solution containing 43.55 g (0.127 mol) of (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide in 71 ml of tetrahydrofuran (THF) is prepared and cooled to 4° C. 138 ml (0.138 mol) of a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran is added dropwise to the first solution. The resulting mixture is stirred for 15 minutes at 20° C. 23.7 g (0.149 mol) of 2,4-difluoro-3-nitropyridine in 10 ml of tetrahydrofuran is then added and the mixture heated at 65° C. for 1 hour. The mixture is cooled to room temperature and partitioned between 150 ml of water and 300 ml of ethyl acetate. The layers are separated. The organic layer is washed twice with 150 ml of water, once with 100 ml of brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is slurried with 100 ml of methanol, then with 150 ml of heptane and then with 60 ml of methanol. The residue is vacuum dried at room temperature with a nitrogen bleed to afford (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide (51.1 g, 83.4% yield. 97.6 A% (HPLC)) as a white solid. MS (ion spray)(relative intensity) 484/486 (75), 312 (100).