Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11](O)=[O:12]>>[Br:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([Cl:3])=[O:12]
Reactant: O=C(O)COc1cccc(Br)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COc1cccc(Br)c1

Procedure:
Thionyl chloride (5 ml, 70 mmol) is added at ambient temperature to 3-bromophenoxyacetic acid (5.77 g, 25 mmol). The reaction mixture is brought to reflux for 2 hours. After returning to ambient temperature, it evaporates and the acid chloride is used. The 3-bromophenoxyacetyl chloride previously obtained is dissolved in dichloromethane (150 ml) and added to a solution of aluminum chloride (6.7 g, 50 mmol) in 50 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 30 minutes and then poured into a an equal volume water-ice mixture (400 ml). The mixture is extracted with dichloromethane, dried over MgSO4 filtered and evaporated. The raw product is purified by flash chromatography on silica (eluent petroleum ether ether=100:10). 0.96 g of 6-bromo-3-coumarone is obtained (yield=18%) of formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CI.[C:12]([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH3CN (700 mL) was added CH3I (110 g, 0.78 mol) and K2CO3 (180 g, 1.3 mol). The mixture was stirred at 25° C. overnight. The solid was filtered off and the filtrate was evaporated under vacuum to give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=7.8 Hz, 1H), 6.74-6.69 (m, 2H), 3.88 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[OH:29][CH2:30][C:31]([CH3:41])([CH3:40])[O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:39][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:31]([CH3:41])([CH3:40])[CH2:30][OH:29])=[CH:38][CH:37]=1)[CH3:28]
Reactant: CC(C)(CO)Oc1ccc(O)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(OC(C)(C)CO)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.52 g), 4-(2-hydroxy-1,1-dimethylethoxy)phenol (0.32 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.36 g, 58%).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[H][H]>C(O)(=O)C.[Ni]>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[CH:23]1[CH:14]([CH2:15][C:16]2[C:21]([NH:22]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CC2Cc3ccccc3NC12
Temperature: 25 °C
Yield: 97 %

Procedure:
In a 350 mL high pressure autoclave, 6 g (17.2 mmol) of camptothecin was suspended in 60 mL of acetic acid, and into which 1.2 g of stabilized nickel catalyst (N113) was added. After hydrogen substitution of the inside atmosphere, the suspension was heated at 110° C. under 2.0 MPa for 6 hours with stirring, whereat the starting material disappeared. The reaction liquid was cooled off to room temperature, filtered on 0.5 g of Celite and washed with 10 mL of acetic acid. An HPLC analysis of this solution confirmed that this Example could produce 1,2,6,7-tetrahydrocamptothecin at an yield of 97% (The diastereoisomeric ratio was 23:74).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][C:57](=[O:59])[CH3:58].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(=O)CCCl
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 65 °C
Yield: 60.6 %

Procedure:
To a solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.083 mmol) in DMF (4 mL) was added 4-chlorobutan-2-one (11 mg, 0.1 mmol) followed by K2CO3 (34 mg, 0.25 mmol). The mixture was heated at 65° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 61%). After drying, the crude was used into the next step without further purification. LCMS: (M+H)+=795.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:34])[C@@H:14]([NH:23][C:24](OCC1C=CC=CC=1)=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:36]([O:43][C:44]([NH:46][C@H:47](C(O)=O)[CH2:48][C:49](=[O:51])[NH2:50])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:35])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:34])[C@@H:14]([NH:23][C:24](=[O:25])[C@H:47]([CH2:48][C:49](=[O:51])[NH2:50])[NH:46][C:44]([O:43][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:45])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccc(F)cc1)NC(=O)OCc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccc(F)cc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 36 %

Procedure:
A solution of 270 mg of N-[3(S)-(benzyloxyformamido)-4-(4-fluorophenyl)-2(R)-hydroxybutyl]-L-proline tert.butyl ester in 50 ml of ethanol was hydrogenated over 30 mg of 10% palladium-on-carbon for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give an oil which was coupled with 158 mg of N-(benzyloxycarbonyl)-L-asparagine in a manner analogous to that described in Example 1. The crude product was chromatographed on silica gel using 10% methanol in dichloromethane for the elution. There were obtained 120 mg of N-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-4-(4-fluorophenyl)-2(R)-hydroxybutyl]-L-proline tert.butyl ester as a white solid of melting point 163°-164° C.
Reaction SMILES: C([O:7][C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[C:19]([O:21]C)=O)(=O)C(C)(C)C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>CO>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:19]([C:9]2[N:10]=[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][N:12]3[C:13](=[O:14])[C:8]=2[OH:7])=[O:21])=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc2ccccn2c(=O)c1OC(=O)C(C)(C)C
Reactant: NCc1ccc(F)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1nc2ccccn2c(=O)c1O
Temperature: 60 °C

Procedure:
Methyl 3-[(pivaloyl)oxy]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate was dissolved in methanol. p-Fluorobenzylamine (2 eqs.) was added and the reaction was stirred and heated to 60° C. for 2 hours. A precipitate had formed and further methanol and 1 eq. of triethylamine were added. After 2 more hours at 60° C. the reaction mixture was partitioned between EtOAc and 1 M HCl. The organic phase was extracted with 0.1 M aqueous NaOH. The aqueous phase was separated and acidified with 1 M HCl. The aqueous phase was extracted with EtOAc and the organic phase was dried over Na2SO4, filtered and concentrated to dryness. The title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:31]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:13]([CH3:31])[CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)/C=C/c1ccc(C#N)cc1)C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
120.0 mg (0.30 mmol) of (2E)-3-(4-cyanophenyl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethyl}acrylamide from Synthesis Example 1, Stage 1 were initially charged in 2 ml of N,N-dimethylformamide and admixed at 0° C. with 19.7 mg (0.45 mmol) of sodium hydride (55% oil dispersion). After addition of 64.1 mg (0.45 mmol) of methyl iodide, the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed three times with water and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the residue purified by preparative HPLC (solvent=water (A)+acetonitrile (B), gradient=40 min. from 10% B to 100% B, flow=18 ml/min).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[CH3:22][S:19]([C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:10][C:14]2=[N:15][CH:16]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccccn1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ccccn3)cc2c1
Yield: 95.5 %

Procedure:
To a solution of the compound obtained in Example 5 (3) (3.8 mg) in methanol (0.5 ml), a 1N aqueous potassium hydroxide solution (2 ml) was added and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction solution was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was poured into a phosphorate buffer (pH 7.0), extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform methanol=50:1) to obtain 2.4 mg of the desired product as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([N:13]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[O:12])=[C:4]2[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:80][C:81]1[CH:82]=[C:83]([CH:86]=[C:87]([C@H:89]2[CH2:93][C@H:92]([F:94])[CH2:91][NH:90]2)[CH:88]=1)[C:84]#[N:85]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:84]([C:83]1[CH:86]=[C:87]([C@H:89]2[CH2:93][C@H:92]([F:94])[CH2:91][N:90]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([N:13]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[O:12])=[C:4]3[CH:3]=2)[CH:88]=[C:81]([F:80])[CH:82]=1)#[N:85]
Reactant: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(Br)cc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](F)C[C@@H]4c4cc(F)cc(C#N)c4)cc23)cc1
Temperature: 140 °C

Procedure:
A N2 purged flask was charged with 5-bromo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-26) (25 mg, 0.05 mmol), palladium acetate (1.0 mg, 5.1 μmol), xantphos (4.5 mg, 7.8 μmol), cesium carbonate (24 mg, 0.07 mmol), 1,4-dioxane (0.25 mL) and 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15) (11 mg, 0.05 mmol). The contents were heated to 140° C. for 30 minutes under microwave irradiation. Upon cooling to room temperature the reaction was partitioned with EtOAc and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=7.6 Hz, 1 H), 7.78 (s, 1 H), 7.38 (s, 1 H), 7.30-7.26 (m, 1 H), 7.25-7.23 (m, 1 H), 7.22-7.16 (m, 5 H), 6.92-6.87 (m, 4 H), 6.16 (dd, J=2.4, 7.6 Hz, 1 H), 5.40 (d, J=52.4 Hz, 1 H), 5.09 (dd, J=6.8, 9.2 Hz, 1 H), 4.74 (d, J=16.0 Hz, 2 H), 4.50 (d, J=15.6 Hz, 2 H), 4.22-3.94 (m, 2 H), 3.82 (s, 6 H), 2.96-2.84 (m, 1 H), 2.07 (dddd, J=4.0, 9.6, 13.6, 40.0 Hz, 1 H). MS m/z 608.1 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]([F:37])([F:36])[CH2:34]I.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:34][C:33]([F:37])([F:36])[F:32]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC(F)(F)F
Temperature: 80 °C

Procedure:
A 0.23 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.28 g of potassium carbonate were dissolved in 5 ml of dimethylformamide. A 0.29 g quantity of 1,1,1-trifluoro-2-iodoethane was added thereto, and the mixture was stirred with heating at 80° C. overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=1:1) to give 0.14 g of white powdery 3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=O)[CH2:7][CH:6]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:3]1[CH2:4][CH2:5]2.C1(C)C=CC(S(NN)(=O)=O)=CC=1.C([BH3-])#N.[Na+].S1(CCCC1)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.O.C1CCCCC1.CN(C)C=O>[CH3:1][CH:2]1[CH2:8][CH2:7][CH:6]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:3]1[CH2:4][CH2:5]2
Reactant: CC1C(=O)CC2CCC1N2c1ccc(C#N)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCC2CCC1N2c1ccc(C#N)c2ccccc12
Temperature: 110 °C
Yield: 22.9 %

Procedure:
159JP84 (115 mg, 0.40 mmol) and p-toluenesulfonhydrazide (90 mg, 0.48 mmol) in absolute ethanol (1.0 mL) were refluxed overnight and the resulting white precipitate was filtered off, dried in vacuo and added to a vial containing sodium cyanoborohydride (101 mg, 1.60 mmol), N,N-dimethylformamide (2.0 mL), sulfolane (2.0 mL), p-toluenesulfonic acid (25 mg) and cyclohexane (2.0 mL). The resulting solution was heated at 110° C. for 2 days, poured into water (200 mL), extracted with ethyl acetate (2×200 mL), dried over Na2SO4, filtered, concentrated in vacuo and purified by preparative TLC (ethyl acetate/n-heptane 1:5, 5× eluted) to afford the title compound (25.3 mg, 22%) as thick oil.
Reaction SMILES: C[N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.BrC1C=C[C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.[Cu](C#N)C#N.N>O>[NH2:13][C:12]1[CH:3]=[CH:4][C:5]([C:6]#[N:2])=[CH:10][C:11]=1[CH3:16]
Reactant: Cc1cc(Br)ccc1N
Reactant: CN1CCCC1=O
Agent: N#C[Cu]C#N
Agent: N
Solvent: O
Product: Cc1cc(C#N)ccc1N
Temperature: 200 °C

Procedure:
To an N-methylpyrrolidone (0.5 L) solution of 4-bromo-2-methylaniline (40 g) was added copper cyanide (38.5 g). The stirred mixture was heated at 200° C. for 2.5 hrs. The mixture was cooled to room temperature then water (1.9 L) and ammonia (0.5 L, 32%) were added. The mixture was extracted with ethyl acetate (2×1.2 L) and the combined organic phases then washed with a mixture of water/ammonia (0.5 L+0.2 L, 32%) and dried over Na2SO4. The solvent was evaporated under vacuum to give the title compound as a brown solid (27.5 g). This material was used in the next step without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([N:9]1[C:16](=[O:17])[CH2:15][C:13](=O)[NH:12][C:10]1=[O:11])([CH3:8])[CH3:7]>O>[CH:6]([N:9]1[C:16](=[O:17])[CH:15]=[C:13]([Cl:3])[NH:12][C:10]1=[O:11])([CH3:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)N1C(=O)CC(=O)NC1=O
Solvent: O
Product: CC(C)n1c(=O)cc(Cl)[nH]c1=O

Procedure:
350 ml of phosphorus oxychloride containing 15 ml of water are slowly run into 75 g (0.44 mole) of 1-isopropyl barbituric acid. After the violent exothermic reaction has abated, the reaction mixture is refluxed for 1 hour. The excess POCl3 is removed by evaporation in vacuo and the oily residue is poured onto ice, giving a precipitate which is filtered, washed with ice water and dried. 55 g of yellowish crystals are thus obtained.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:21]2[S:22][CH:23]=[C:24]([Br:26])[CH:25]=2)[CH2:18][CH2:17][O:16][CH2:15][C@H:14]1[CH2:19][OH:20]>ClCCl>[C:1]([NH:9][C:10]([NH:12][C@@:13]1([C:21]2[S:22][CH:23]=[C:24]([Br:26])[CH:25]=2)[CH2:18][CH2:17][O:16][CH2:15][C@H:14]1[CH2:19][OH:20])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@]1(c2cc(Br)cs2)CCOC[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)cs2)CCOC[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl isothiocyanate (66.5 μL) was added to a solution of (±)-[(3R*,4S*)-4-amino-4-(4-bromo-thiophen-2-yl)-tetrahydro-pyran-3-yl]methanol (144 mg) in dichloromethane (5 mL). The mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (233 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][C:51]=1[Cl:57]>CN(C=O)C.C(O)=O>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:51]([Cl:57])[CH:52]=1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: NCc1ccc(O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=CO
Product: Cc1sc(C(=O)NCc2ccc(O)cc2Cl)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-3-chloro-phenol hydrochloride (104 mg, 0.55 mmol) and ethyl-diisopropylamine (94 mL, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2-chloro-benzylamide (51 mg) as a colourless oil. LC-MS: tR=1.01 min, [M+1]+=362.13.
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[OH-].[Na+]>CO>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:26])=[O:2])[CH:15]=[CH:14]2
Reactant: COC(=O)/C=C/c1ccc2cc(OC)ccc2c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2c(/C=C/C(=O)O)ccc3cc(OC)ccc23)cc1
Yield: 92.6 %

Procedure:
As in Example 112, (E)-3-[6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid methyl ester (1.8 g) in methanol (10 mL) was heated at reflux with 1N sodium hydroxide solution (8 mL) for 1 hour. The usual work up provided 1.6 g of (E)-3-[6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid. Crystallization of a small portion from dichloromethane-ethyl acetate gave the analytical sample, mp 248°-249° C. Anal. Calcd for C21H18O4 : C, 75.43; H, 5.43 Found: C, 75.65; H, 5.70