Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:7]3[C:2]([F:1])=[CH:3][C:4]([N+:19]([O-:21])=[O:20])=[C:5]([NH:9][C@H:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH3:11])[N:6]=3)[CH:26]=2)[CH2:24][CH2:23]1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 55 °C
Yield: 66.2 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 23, 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature was added 5-cyclopropyl-1H-pyrazol-3-amine (0.50 g, 4.0 mmol), and DIEA (0.26 g, 2.0 mmol). The reaction was then heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was then extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.53 g, 66%). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=11.1 Hz, 1H), 7.38-7.35 (m, 2H), 7.07-7.02 (m, 2H), 6.17 (s, 1H), 5.41-5.39 (m, 1H), 1.93-1.87 (m, 1H), 1.61 (d, J=7.0 Hz, 3), 1.02-1.00 (m, 2H), 0.69-0.66 (m, 2H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(C)C=CC=CC=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(N)[C@@H](N)C(C)C)=CC=1>CC(O)(C)C.CC(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([OH:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: COc1ccc(C(N)(c2ccc(OC)cc2)[C@@H](N)C(C)C)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 99 %

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanone (46.8 g, 223.3 mmol) and 1.0 M KOtBu (4.47 mL, 4.47 mmol) in t-BuOH in IPA (136 mL) and toluene (34 mL) in a autoclave was added dichloro{(S)-(−)-2,2′-bis[di(3,5-xylyl)-phosphino-1,1′-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine (0.273 g, 0.22 mmol) (Strem Chemicals). The reaction mixture was degassed by three vacuum-filling with nitrogen cycles. Hydrogen was introduced into the autoclave at a pressure of 300 psi and then reduced to 20 psi by slowly releasing the stop valve. After this procedure was repeated three times, the autoclave was pressurized to 300 psi with hydrogen. The reaction mixture was vigorously stirred at ambient temperature for 4 days (pressure was recharged to 300 psi when the internal pressure dropped below 200 psi). The pressure was released and the solvent was removed under reduced pressure. Ethyl acetate (300 mL) and 10% citric acid solution (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 DCM/ethyl acetate) to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (46.76 g, 99.0%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 86.4% e.e. (S)-enantiomer). (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoro ethanol (97.8 g, 462 mmol, 76% e.e.) was dissolved in 4.5% ethyl acetate/hexane (v/v) (2170 mL) with heating to reflux. After complete dissolution, it was slowly cooled to ambient temperature overnight. The resulting solid was collected by filtration, washed with hexane and dried to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (62.5 g, 63.9%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 98.8% e.e. (S)-enantiomer).
Reaction SMILES: [N:1]1([C:6]2C=CN=[C:8]([CH3:12])[CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Cl:14][C:15]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:16]=1[CH:17]=[N+:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.ClC1C=CC=C(F)C=1C=O.[NH:38]1CC[CH2:40][CH2:39]1>>[Cl:14][C:15]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:16]=1[CH:17]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:5]1[N:1]([CH2:6][C:7]2[CH:8]=[CH:12][CH:40]=[CH:39][N:38]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: Fc1cccc(Cl)c1C=[N+]1CCCC1
Reactant: C1CCNC1
Reactant: Cc1cc(-n2cccc2)ccn1
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: Fc1cccc(Cl)c1C(c1cccn1Cc1ccccn1)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-pyrrol-1-yl-methyl-pyridine and 1-(2-chloro-6-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 2-chloro-6-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O([Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])S(C(F)(F)F)(=O)=O.[Li]CCCC.CCCCCC.[CH3:54][C:55]1[CH:62]=[CH:61][CH:60]=[CH:59][C:56]=1[CH:57]=O>C1COCC1>[C:39]([Si:36]([CH3:38])([CH3:37])[O:8][C:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[CH:54][C:55]2[CH:62]=[CH:61][CH:60]=[CH:59][C:56]=2[CH3:57])[CH:2]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1C=CCCCC1
Reactant: Cc1ccccc1C=O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1C=C1C=C(O[Si](C)(C)C(C)(C)C)CCCC1
Reaction time: 0.5 h

Procedure:
To a solution of cycloheptenone (71.7 mmol) in 220 ml of anhydrous THF there are added, in succession, triphenylphosphine (72.6 mmol) and then, dropwise, tert-butyldimethylsilyl triflate (72.3 mmol), and the whole is stirred at room temperature for 1 hour 30 minutes. The mixture is then brought to −78° C., and a solution of nBuLi/hexane (72 mmol) is added slowly, followed 30 minutes later by 2-methylbenzaldehyde (72.03 mmol). The whole is stirred at that temperature for 30 minutes, and then with the temperature gradually returning to room temperature. After 2 hours 30 minutes, the reaction mixture is precipitated from 2.5 liters of petroleum ether and filtered, and the filtrate is concentrated to dryness. The title product is purified by chromatography over silica gel (100% heptane).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.C(Cl)Cl.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)(Cl)Cl>[CH:19]1[C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=[C:15]([O:14][C:12]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:13])[CH:20]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cncs1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess N-methyl morphcline in 1 DO ml of methylene chloride was cooled to 0° C. and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCl3, washed successively with 1N HCl, saturated aqueous NaHCO3, and saturated brine, dried over NaSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SIO2, 1-2% MeOH/CHCl3, Rf=0.5 in 4% MeOH/CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. NMR (CDCl3) δ5.53 (s, 2H), 7.39 (dt, J=9, 3 Hz, 2H), 8.01 (s, 1H), 8.29 (dr, J=9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)+ =281.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1>[OH:23][CH:22]([C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:4]
Reactant: COc1ccc(C=O)cc1
Reactant: C#CC(=O)OCC=C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#CC(=O)OCC=C(C)C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 10 g (72 mmol) of 3-methyl-2-butenyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 47 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 8.8 ml (72 mmol) of 4-methoxybenzaldehyde in 100 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes, then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 3-methyl-2-butenyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[Li]CCCC.[I:32]I>C(OCC)C.C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][C:13]=1[I:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A solution of (6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester (0.90 g, 3.43 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.29 mL, 8.55 mmol) in 25 mL of anhydrous diethyl ether was cooled to −78° C. under an argon atmosphere. The resulting mixture was treated dropwise with n-BuLi (2.5 M in hexanes, 3.42 mL, 8.55 mmol) over 5 minutes, and the mixture was allowed to warm to −10° C. After 30 minutes, the mixture was cooled to −78° C. and a solution of I2 (1.14 g, 4.5 mmol) in 5 mL of anhydrous THF was added rapidly. The resulting mixture was warmed to room temperature, stirred for 1 hour, and quenched with 50 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified on SiO2 (10% ethyl acetate in dichloromethane) to afford the title compound (150 mg, 11.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[F:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccccc1F
Reactant: Nc1ccc(Br)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccccc1CNc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
In a round bottom flask, 5-bromo-pyridin-2-ylamine (38, 4.05 g g, 23.4 mmol) was combined with 70.0 mL of acetonitrile, 2-fluoro-benzaldehyde (39, 2.45 mL, 23.4 mmol), triethylsilane (20.0 mL, 125 mmol) and trifluoroacetic acid (10.0 mL, 130 mmol). The reaction was stirred at 80° C. for 3 hours. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-60% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (40, 5.0 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (350 mg) in THF (6.2 ml) at -78° C. was added L-Selectride (342 μl, 1 eq.) dropwise over 30 minutes. The reaction was stirred for a further 15 minutes after addition and then quenched by pouting into saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 60% hexane:40% ethyl acetate to give the desired product (216 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.Cl.[N:40]1([CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:55][C:52]1[CH:53]=[CH:54][C:49]([O:48][CH2:47][CH2:46][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:50][CH:51]=1)=[N:6]2
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(OCCN4CCCCC4)cc3)ncc12
Yield: 8.2 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), (4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)amine hydrochloride (45 mg, 0.17 mmol), triethylamine (0.024 mL, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-7-phenyl-N-(4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (6 mg) as a yellow solid. MS m/z 429 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:37]=[CH:38][C:39]2[N:44]=[C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([OH:52])=[C:47]([CH3:53])[CH:46]=3)[O:42][C:40]=2[N:41]=1.O[CH:59]1[CH2:62][CH:61]([C:63]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])[CH2:60]1>O1CCCC1.C(N(CC)CC)C>[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:37]=[CH:38][C:39]2[N:44]=[C:43]([C:45]3[CH:46]=[C:47]([CH3:53])[C:48]([O:52][CH:59]4[CH2:62][CH:61]([C:63]([O:65][CH2:66][C:67]5[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=5)=[O:64])[CH2:60]4)=[C:49]([CH3:51])[CH:50]=3)[O:42][C:40]=2[N:41]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
At 0° C., 179 mg of triphenylphosphine and 107 μl of diethyl azodicarboxylate were initially charged in 4.5 ml of tetrahydrofuran, and the mixture was stirred for 15 min. 200 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenol, 95 μl of triethylamine and 141 mg of benzyl 3-hydroxycyclobutanecarboxylate were then added to the reaction, and the reaction was stirred under argon, initially at room temperature for 3 h. Another 179 mg of triphenylphosphine and 107 μl of diethyl azodicarboxylate were then added, and the reaction was stirred for 12 h. For work-up, the reaction was concentrated and the resulting residue was purified by flash chromatography (silica gel, heptane/ethyl acetate). This gave 216 mg (70%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:28]3[CH:27]=[CH:26][C:25]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:24]([F:23])[CH:29]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccc(-c4ccccc4)c(F)c3)o2)c1
Temperature: 85 °C

Procedure:
The furyl bromide (99)(100 mg, 0.28 mmol) was coupled to 2-Fluoro-biphenyl-4-boronic acid (65 mg, 0.30 mmol) acid using Method E, except that the reaction was heated at 85° C. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=CC=C[CH:17]=1.B(O)O>C1(C)C=CC=CC=1.O.CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:21])=[CH2:17]
Reactant: COC(=O)c1ccc(Br)c(S(C)(=O)=O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1ccc(C(=O)OC)cc1S(C)(=O)=O
Yield: 189.8 %

Procedure:
23 mmol of methyl 4-bromo-3-methylsulfonylbenzoate, 54 mmol of Na2 CO3, 2.9 mmol of triphenylphosphine and 1.5 mmol of Pd(OAc)2 are stirred intensively at RT for 5 min in 200 ml of toluene and 15 ml of H2O. A solution of 23 mmol of boronic acid according to Preliminary Stage 1 is then added in 50 ml of EtOH and the mixture is boiled under reflux for 1.5 h. After phase separation, the organic phase is washed twice with 50 ml of NaCl solution and the aqueous phase is extracted twice with 100 ml of EA. The combined organic phases are dried over Na2 SO4, the solvents are removed in vacuo and the residue is chromatographed on silica gel using DIP. 1.4 g of a colorless oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([S:7][CH2:8][CH2:9][CH3:10])[CH3:6].[CH2:12](O)[CH:13](C)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][CH:5]([S:7][CH2:8][CH2:9][CH3:10])[CH3:6])[CH:13]([CH3:14])[CH3:12]
Reactant: CC(C)CO
Reactant: CCCSC(C)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCSC(C)CC(=O)OCC(C)C

Procedure:
Into a 25 cc micro flask equipped with spin bar, hot plate (equipped with magnetic stirrer), reflux condenser and thermometer are placed 5 grams (0.0284 moles) of methyl-3-(propylthio)butyrate; 8.4 grams (0.1136 moles) of isobutyl alcohol and 0.05 grams of para-toluene sulfonic acid. With stirring, the reaction mass is heated to reflux and refluxed for a period of 14 hours. At the end of the 14 hour period, the reaction mass is cooled and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:7]2[CH2:8][CH2:9][C@@H:10]([CH3:12])[CH2:11][C@H:6]2[O:5][CH2:4][S:3]1.C([Li])CCC.[CH3:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[OH:25][C@@:20]([C@H:4]1[S:3][C:2]([CH3:13])([CH3:1])[C@@H:7]2[CH2:8][CH2:9][C@@H:10]([CH3:12])[CH2:11][C@H:6]2[O:5]1)([CH2:21][CH2:22][CH2:23][CH3:24])[CH3:19]
Reactant: C[C@@H]1CC[C@@H]2[C@@H](C1)OCSC2(C)C
Reactant: CCCCC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[C@@](C)(O)[C@@H]1O[C@@H]2C[C@H](C)CC[C@H]2C(C)(C)S1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
A vigorously stirred solution of (4aR,7R,8aR)-hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin (9 g, 0.045 mole, prepared as described by ELIEL et al. Org. Synth. 65, 215 [1987]) in 130 ml of anhydrous tetrahydrofuran was cooled to -78° C. under an ar8on atmosphere and butyllithium (3.168 g, 0.0195 mole) dissolved in 32 ml of hexane was added dropwise over a period of 15 minutes. The solution was further stirred for additional 15 minutes. The temperature of the solution was allowed to slowly reach 0° C. and further stirred for 15 minutes. The solution was cooled again to -78° C. under the argon atmosphere, the stirring was continued and 2-hexanone (4.5 g, 0.045 mole) dissolved in 25 ml of anhydrous tetrahydrofuran was added dropwise over a period of 20 minutes. The solution was further stirred for additional 4 hours. The temperature of the solution was allowed to slowly reach the room temperature, 10 ml of water were added dropwise over a period of 10 minutes and then 15 ml of a saturated solution of ammonium chloride in water were added at once. The reaction mixture was S partitioned between diethyl ether and water. The ether portion was washed with brine, dried over anhydrous Na2SO4 which was then removed by filtration, and evaporated to leave 13.1 g of a thick syrup. This thick syrup was dissolved in 10 ml of hexane-ethyl acetate (9:1 v:v) solvent and chromatographed on 1000 g of silica gel (230-400 mesh ASTM). The 5 liters of hexane-ethyl acetate that were eluted, were evaporated in vacuo to leave a viscous colorless liquid residue. This liquid was distilled at reduced pressure. The fraction distilling at 95°-97° C. and 0.05 Torr was collected yielding 6.2 g (45.9%) of the title compound, which shows [α]365 =-28.91° (C=1.61 in CHCl3). Anal. Calcd. for C17H32O2S: C,67.96; H,10.74; O,10.65; S,10.65, Found: C,68.20; H,10.63; O,10.47; S,10.56.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:19])=[NH:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][C:30]([CH3:32])=[O:31]>>[C:30]([OH:2])(=[O:31])[CH3:32].[CH2:21]([NH:20][C:18]1[NH:17][C:15]([NH:14][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:16][C:30]([CH3:32])([CH3:29])[N:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CO
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)NCCc1ccccc1
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCCc2ccccc2)N1

Procedure:
150 ml of methanol, 150 ml of acetone and 0.8 ml of concentrated hydrochloric acid were added to 13.1 g (33.6 mmol) of N1-phenethyl-N5-octyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 150 ml of ethanol, and to the solution were added 100 ml of water and 13 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized two times from ethanol/ether to obtain 4.8 g of colorless crystals having a melting point of 86 to 88° C.