Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][NH2:21].C(O)CCC>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:21][CH2:20][C:19]1[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=1[F:26])=[NH:11]
Reactant: NCc1c(F)cccc1F
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: CCCCO
Solvent: O
Product: N=C(NCc1c(F)cccc1F)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 7.80 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 2.86 g. of 2,6-difluorobenzylamine (prepared from 2,6-difluorobenzylamine hydrochloride) in 100 ml. of n-butanol and 20 ml. of water is heated at reflux for 66 hours. The solvent is removed under reduced pressure and the residual yellow oil is dissolved in aqueous ethanol and made basic with 10N NaOH. The resultant mixture is extracted with chloroform and the chloroform extract is evaporated under reduced pressure to give a yellow gum. This gum in ethyl acetate is purified by silica gel column chromatography, giving a colorless solid. This solid is recrystallized from aqueous ethanol, giving the desired product as colorless crystals, m.p. 168.5°-169.5° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[F:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1F
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (3 g, 7.15 mmol) was dissolved in MeOH (25 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (2.104 mL, 7.15 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.438 mL, 7.15 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (36.8 mL, 221.05 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.12 g, 76%) was isolated as a colourless oil. MS m/z 389 (M+H)+
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].O>B(F)(F)F.CCOCC>[C:1]([C:16]1[C:17]([OH:19])=[CH:18][C:9]([OH:8])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(C(C)=O)c(O)cc1O
Temperature: 25 °C
Yield: 41.6 %

Procedure:
Acetic anhydride (3.06 g, 30.0 mmol) was added to methyl 2,4-dihydroxybenzoate (5.04 g, 30.0 mmol) in boron trifluoride diethyl etherate (7.6 ml) and the mixture was stirred and held at reflux for 3 hours and then allowed to cool to room temperature. Water (80 ml) was added and the mixture stirred at room temperature for 30 minutes. The resulting yellow solid was removed by filtration and sucked as dry as possible under vacuum. The solid was dissolved in dichloromethane and was washed with water, the organic layer was separated and the solvent removed in vacuo to afford methyl 5-acetyl-2,4-dihydroxybenzoate as a bright yellow solid (2.62 g, 42%) which was used without further purification. 1H NMR (DMSO-d6) 12.58 (1H, s), 11.22 (1H, s), 8.33 (1H, s), 6.45 (1H, s), 3.90 (3H, s), 2.62 (3H, s). MS: [M+H]+ 211.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17]C=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=COCCOCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCOCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In methanol (10 ml) was dissolved 2-[1-[(4-chlorophenyl)sulfonyl]-3-(2-vinyloxyethoxy)propyl]-1,4-difluorobenzene (123 mg, 0.295 mmol). P-toluenesulfonic acid monohydrate (2.0 mg, 0.011 mmol) was added and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, the residue was purified by silica gel chromatography (methylene chloride:methanol=50:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (80 mg, 70%) was obtained as a white powder.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].[C:17]1([PH:23][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>C1(C)C=CC=CC=1.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>[C:24]1([P:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=[O:12])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: O=Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 12 h

Procedure:
After 5.9 ml of triethylamine (43 mmol) and 334 mg of tetrakis(triphenylphosphine)palladium have been added, 5 ml of 2-bromobenzaldehyde (43 mmol) and 11.15 ml of diphenylphosphine (64.5 mmol) are refluxed in 150 ml of absolute toluene under a protective gas atmosphere in a three-necked flask equipped with a reflux condenser. Triethylamine hydrobromide precipitates as a white solid over the course of the reaction. After 12 hours, the reaction solution is filtered, washed three times with saturated ammonium hydrochloride solution and saturated sodium chloride solution and the solvent is removed in a rotary evaporator. The resultant crude product is recrystallised from methanol. Yield 10.61 g (85% of theoretical).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:19][C:20](=[O:21])[C:15]2=[C:14]([CH3:28])[NH:13]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2[S:55](Cl)(=[O:57])=[O:56])[CH:48]=[CH:47][CH:46]=1>N1C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:55]([C:53]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:54]=2[N:45]=[CH:46][CH:47]=[CH:48]3)(=[O:56])=[O:57])=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:19][C:20](=[O:21])[C:15]2=[C:14]([CH3:28])[NH:13]1
Reactant: Cc1[nH]n(Cc2cc(N)ccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1[nH]n(Cc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.5 %

Procedure:
A solution of 1-(2-chloro-5-aminophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one dihydrochloride salt (0.55 g, 1.4 mmol), pyridine (10 ml) and triethylamine (0.18 ml, 1.36 mmol) was stirred at 0° C. under argon for 20 minutes and dimethylaminopyridine (0.016 g, 0.14 mmol) and 8-quinoline sulfonyl chloride (0.37 g, 1.6 mmol) were added. The mixture was stirred at 0° C. for 2.5 hours and poured into ice-water with stirring. The product was collected by filtration to afford 0.66 g (88%) of 1-[2-chloro-5-((8-quinolinylsulfonyl)amino)phenylmethyl]-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a tan powder, m.p. 325° C. (dec.) when dried at 100° C. for 24 hours in high vacuum.
Reaction SMILES: [C:1]1(=[N:7][OH:8])CCC[CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>C(Cl)Cl>[N:7]([CH:1]([O:18][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=1)[CH2:2][CH3:3])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: ON=C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CCC(N=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of cyclohexanone oxime (3.11 g, 42.58 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (18.88 g, 42.58 mmol) and 4-nitrobenzoic acid (71.16 g, 425.8 mmol) in methylene chloride (300 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL) and 3% sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was recrystalized in diethyl ether/petroleum ether (1:1) in a −5° C. freezer to give 1-Nitroso-1-para-nitrobenzoxypropane as bright blue crystals (25-30% yield): Rf 0.5 (pentane/ethyl acetate=20:1); 1H NMR (300 MHz, CDCl3) δ 1.69 (s, 6H), 8.31-8.48 (d, 4H); 13C NMR (300 MHz, CDCl3) δ 21.1 (2CH3), 122.6 (O—C—N), 124.0 (2Ph-CH), 131.4 (2Ph-CH), 135.6 (Ph-C), 151.2 (Ph-C), 162.9 (C═O).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:22][CH2:23][CH2:24][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:21]
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Reactant: OCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2scc(Cn3c(=O)n(CCBr)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To the stirred solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (100 mg, 0.34 mmol), 2-Bromo-ethanol (0.03 mL, 0.41 mmol) and triphenylphosphine (107 mg, 0.41 mmol) in THF (2.0 mL) is added DIAD (0.082 mL, 0.41 mmol) in a dropwise manner. The mixture is stirred at room temperature for 20 hr and then another 0.03 mL of 2-Bromo-ethanol, 107 mg of triphenylphosphine and 0.08 mL of DIAD are added. The reaction is continued for another 24 hr and then the solvent is removed under vacuum and the residue is purified by flash column chromatography to give 75 mg (55%) of 1-(2-Bromo-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)=[CH:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCCN
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 63.9 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and putrescine (3.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(4-aminobutylamino)-cholest-7-en-3β-ol as a white solid (6.9 g, 64%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 23% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.061 mMol) propionyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Na]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: [Na]c1ncc[nH]1
Reactant: N#Cc1ccc(F)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)cc1

Procedure:
A mixture 4-fluorobenzonitrile (3 g, 25 mmol) and imidazolyl sodium (2.48 g, 27.5 mmol) in DMF (50 mL) was stirred at 80° C. under Ar for 12 h. Progress of reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and the residue was diluted with 50 mL water and stirred. The aqueous mixture was extracted with EtOAc (2×50 mL). Combined EtOAc extracts was dried over anhydrous MgSO4, concentrated, and the 4-(1-imidazolyl)-benzonitrile was isolated by column chromatography (3.6 g, 78%). LCMS: MH+=170; 1H NMR (CDCl3) δ 8.0 (s, 1H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:3]1.[CH2:15]=[O:16]>>[OH:16][CH2:15][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cn1cnc(SCc2ccccc2)c1
Reactant: C=O
Product: Cn1cnc(SCc2ccccc2)c1CO

Procedure:
The 5-carboxyaldehyde-1-methyl-4-(phenylmethyl)thioimidazole intermediate which is a reactant for the above step (a) can be prepared by steps comprising condensing 1-methyl-4-(phenylmethyl)thioimidazole with formaldehyde under weakly acidic conditions to form 5-hydroxymethyl-1-methyl-4-(phenylmethyl)thioimidazole and oxidizing to form said reactant or by directly formylating 1-methyl-4-(phenylmethyl)thioimidazole to form said reactant.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH:34]([CH3:36])[CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH:34]([CH3:36])[CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:32]
Reactant: CCNC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CCN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1)C(C)C

Procedure:
The product from Example 44E and ethyl(isopropyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.98 (m, 311), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 15H), 1.4 (m, 9H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[Br:17]Br>C(O)(C)C>[Br:17][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11](=[O:16])(=[O:15])[N:12]([CH3:13])[CH3:14])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Reactant: BrBr
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl

Procedure:
7.9 g of 4'-chloro-3'-dimethylsulfamoylacetophenone were reacted according to Example 1a) with 4.8 g of bromine and worked up. Colorless crystals from isopropanol, melting point: 98° C.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:11]Br.[CH2:17]([O:19][C:20]([C@:22]1([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:27]([NH2:28])[CH2:26][C@@H:25]2[C@H:23]1[C@@:24]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[CH3:18].[Cl-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:19][C:20]([C@:22]1([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[C@H:27]([NH:28][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:8]([Cl:7])[CH:9]=2)[CH2:26][C@@H:25]2[C@H:23]1[C@@:24]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[CH3:18]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.3 %

Procedure:
42 μL of pyridine and 123 mg of 3,4-dichlorobenzylbromide were added to 175 mg of (1R,2R,3R,5R,6R)-3-amino-2-t-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.88 mL of chloroform at ice-cooling, and then the mixture was stirred for 3 days at room temperature. A saturated aqueous solution of sodium chloride was added thereto, and the mixture was extracted five times with chloroform. The organic layers were combined and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: chloroform-ethanol=100:1 to 50:1, followed by hexane-ethyl acetate=5:1), thereby yielding 98 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29].C=O.[BH4-].[Na+].[C:34](O)(C(F)(F)F)=O>C1COCC1.CC(=O)OCC>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNC1)C3
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C)C1)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A mixture of Example 68 (150 mg; 0.36 mmol; 1 eq.), formaldehyde (0.27 mL; 3.64 mmol; 10 eq.) and NaBH4 (69 mg; 1.82 mmol; 5 eq.) in THF (12 mL) was cooled to 0° C. and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with EA. The organic phase was washed with 0.1M NaOH (2×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM/MeOH/TEA) afforded the title compound (75 mg, 48%) as white foam. 1H NMR (DMSO-d6) δ 7.47-7.38 (m, 1H), 7.33-7.25 (m, 1H), 7.09-6.99 (m, 2H), 4.99-4.89 (m, 1H), 4.82 (m, 2H), 4.65-4.42 (m, 2H), 2.88-2.75 (m, 4H), 2.62 (s, 1.5H), 2.60-2.52 (m, 2.5H), 2.37-2.20 (m, 2H), 2.19 (s, 1.5H), 2.18 (s, 1.5H), 1.80-1.66 (m, 1H), 1.46-1.31 (m, 1H). HPLC (max plot) 95.6%, Rt 2.63 min. UPLC/MS: (MS+) 426.5 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30].CN1C(=O)CCC1.Cl>O>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1)#[N:30]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(Br)cc4)nc3)cc2)CC1
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)cc4)nc3)cc2)CC1
Temperature: 60 °C

Procedure:
3.3 g of 2-(4'-bromophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine and 0.9 g (0.01 mol) of CuCN were added to 30 cm3 of NMP and the solution was refluxed for 2 hours using a mantle heater. The solution was cooled to 60° C. and added to a solution of 4.4 g of FeCl3.6H2O, 1.3 cm3 of concentrated hydrochloric acid and 6 cm3 of water. The resulting solution was heated on a warm water bath at a temperature of 60° C. for one hour. The crystals deposited were filtered out, washed with water and treated through a silica gel column using chloroform as the solvent. The chloroform was distilled off and the residue was recrystallized from a mixture of acetone and chloroform to yield 2.2 g (0.006 mol) of 2-(4'-cyanophenyl)-5-[4'-(trans-4"-propylcyclohexyl) phenyl] pyrimidine. The phase transition temperature of this compound, measured by DSC, was: ##STR28## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH3:13])[CH:5]=1)([O-:3])=[O:2].CC1C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].CO>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[O:9][CH:26]=[N:25][CH:24]=2)=[C:6]([O:12][CH3:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-c1cnco1
Temperature: 64 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a 5 L three necked round bottom flask equipped with a condenser and a mechanical stirrer was placed 1B (146.3 g, 0.8076 mol), TOSMIC (157.7 g, 0.8077 mol), K2CO3 (116.6 g, 0.8075 mol) and MeOH (2.5 L). The mixture was heated to reflux under N2 and stirred for 3 hours. Water (1.25 L) was added drop-wise while maintaining the pot temperature between 59-69° C. The resulting slurry was cooled to room temperature, and then to 5° C. with an ice-water bath. After stirring for 30 minutes at 5° C., the slurry was filtered. The resulting cake was washed with water (3×400 mL) and dried in a vacuum oven at 45° C. for 20 hours to give 5-(4-nitro-2-methoxyphenyl)oxazole (1C, 148.5 g, 84%) as a yellow-reddish solid. 1H NMR (CDCl3) d 8.02 (s, 1H), 7.97 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 4.11 (s, 3H).