Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:23]=4)=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:17]=[N:16][C:15]2[C:10]([N:9]=1)=[CH:11][C:12]([C:18]1[CH:23]=[C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:21]=[N:20][CH:19]=1)=[CH:13][CH:14]=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CNCCN1c1cnc2ccc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 1,1-dimethylethyl 3-oxo-4-(7-{5-[(phenylsulfonyl)amino]-3-pyridinyl}-2-quinoxalinyl)-1-piperazinecarboxylate (0.21 mmol) in acetonitrile (4 ml) was added concentrated trifluoroacetic acid (4 ml). The reaction stirred at ambient temperature for 1 hour and was then concentrated to an orange oil. The residue was neutralized with saturated sodium bicarbonate solution upon which a precipitate formed. The precipitate was dissolved in ethyl acetate and crashed out of solution with hexanes, which was filtered and dried to afford the title compound (66 mg, 67%) as an off-white solid. MS(ES)+ m/e 461.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl.CCCCCCC.ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([S:14]([Cl:13])(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:11])([F:10])[F:12]
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=S(=O)(Cl)c1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5° C., 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent gave 2.19 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.[CH:15]([Mg]Br)=[CH2:16].[NH4+].[Cl-]>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]2[C:7]=1[NH:12][CH:16]=[CH:15]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(OCCCl)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: ClCCOc1ccc(Cl)c2[nH]ccc12
Reaction time: 2.25 h
Yield: 158.3 %

Procedure:
To a solution of 1-(2-chloroethoxy)-4-chloro-3-nitrobenzene (10.00 g, 0.04236 mol) in THF (230 mL) stirred in a cold bath at -50° to -40° C. was added a THF solution of vinylmagnesium bromide (132 mL, 1.0M, 0.132 mol) over 2 minutes. After stirring in the cold bath for 2-2.5 hours, saturated NH4Cl (150 mL) was added to the cold solution and it was removed from the cold bath. 1M HCl was added to dissolve the precipitated solids and the mixture was stirred for 0.5 hour. The layers were separated and the aqueous phase was extracted once with diethyl ether (80 mL). The organic layer combined and dried over anhydrous magnesium sulfate, filtered and the solvent evaporated to give 15.43 g of a dark oil. Purification by chromatography (hexanesmethylene chloride, 2:1) afforded a solid which was triturated with hexane and filtered to afford the product as yellowish white solid: 3.51 g (36%); mp 73-°75 ° C.; MS El m/e 229, 231, 233 (M+);1H NMR (400 MHz, DMSO-d6) δ 3.99 (t, 2H;, J=5.1 Hz), 4.34 (t, 2H, J=5.0 Hz), 6.51 (t, 1H, J=2.7 Hz), 6.53 (d, 1H, J=7.8 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.29 (t, 1H, J=2.7 Hz), 11.43 (s, 1H).
Reaction SMILES: [CH3:1][S:2][CH3:3].[SH:4][CH2:5][CH2:6][S:7][CH2:8]CS.C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>O>[CH3:1][S:2][CH2:3][CH2:8][S:7][CH2:6][CH2:5][S:4][C:22](=[O:25])[CH:23]=[CH2:24]
Reactant: CSC
Reactant: SCCSCCS
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)SCCSCCSC
Temperature: 0 °C
Yield: 103.9 %

Procedure:
Three-necked flask fitted with a thermometer, a stirrer and a dropping funnel was charged with 16.8 g (0.10 mole) of di(2-mercaptoethyl)sulfide monomethyl thioether, 11.1 g (0.11 mole) of triethylamine, and 100 ml of anhydrous chloroform, and the mixture was cooled to 0° C. With stirring, 10.0 g (0.11 mole) of acryloyl chloride was gradually added dropwise. At this time, the reaction temperature was maintained at 0° to 5° C. After the end of addition, the mixture was further stirred at 20° C. for 1 hour. Then, the reaction mixture was poured into water. The organic layer was washed with a dilute aqueous solution of sodium carbonate, and then with water. The organic layer was dried over anhydrous magnesium sulfate. The resulting oil was purified by column chromatography (filler: silica gel; developing agent: chloroform) to give 23.1 g of acryloylthioethyl 2-methylthioethyl sulfide as a colorless clear oil. This compound had a refractive index of 1.585. In its IR spectrum, a strong absorption based on the carbonyl group at 1765 cm-1 and an absorption based on the terminal double bond at 1640 cm-1 were observed. Its elemental analysis values (the parenthesized values were calculated values) well agreed with the calculated values. C: 43.26 % (43.21%), H: 6.58% (6.36%), S: 42.98% (43.26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:48]1([NH:51][CH2:52][C@H:53]2[NH:57][CH2:56][C@H:55]([OH:58])[CH2:54]2)[CH2:50][CH2:49]1>CN(C=O)C>[CH:48]1([NH:51][CH2:52][C@@H:53]2[CH2:54][C@@H:55]([OH:58])[CH2:56][N:57]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:50][CH2:49]1
Reactant: O[C@H]1CN[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1C[C@H](O)C[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (250 mg, 0.5 mmol), HOBt (81 mg, 1.2 eq.), EDC (115 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (3R, 5S)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (312 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight, followed by heating at 45° C. for 5 hours. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[CH2:14])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]([C:19]#[C:20][C:21]([O:23][CH3:24])=[O:22])=[O:18].CCCCCC.CCOC(C)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH3:15][O:16][C:17]([C:19]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=[C:6]2[C:5]=1[CH:4]=[C:3]([O:2][CH3:1])[C:12]1[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:18]
Reactant: C=Cc1ccc(OC)c2ccccc12
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccc2c(cc(OC)c3ccccc32)c1C(=O)OC
Yield: 61.2 %

Procedure:
1-methoxy-4-vinyl naphthalene 18.42 g (0.1 mol) and acetylene dicarboxylic acid dimethyl ester 28.42 g (0.2 mol) were dissolved in nitrobenzene, 200 ml, and they were reacted for 7 hours at the temperature of 130° C. After cooling, nitrobenzene was escaped in vapor under a reduced pressure condition, silica gel column chromatography (developing solvent n-hexane:an acetic acid ethyl=9:1) process was performed to residual elements, crude material, 23.08 g, was obtained. Further, objective phenanthrene compounds, 19.85 g (yield 61.2%) was obtained by recrystallizing from n-butanol. A melting point was 150.2 to 151.0° C. An infrared absorption spectrum of this phenanthrene compound is shown in FIG. 4.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.[O:36]=[O+][O-].[BH4-].[Na+]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:4]2([CH2:1][CH2:2][OH:36])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[CH:15][CH:14]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:21][CH:22]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O=[O+][O-]
Reactant: OB(O)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and pyridine-3-boronic acid using a procedure analogous to that described in Example 1 Step 2 followed by treatment with (i) ozone and (ii) NaBH4. LC-MS Method 2 tR=1.412, min, m/z=421.2; 1H NMR (CDCl3) 1.52 (d, 3H), 2.03-2.17 (m, 3H), 2.22-2.32 (m, 3H), 2.81 (m, 1H), 3.47-3.52 (m, 1H), 3.72 (m, 1H), 5.63 (m, 1H), 6.93-7.01 (m, 4H), 7.21-7.26 (m, 2H), 7.28-7.33 (m, 3H), 7.73 (m, 1H), 8.51 (m, 1H), 8.68 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.[CH3:19][N:20](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH3:12][O:11][C:9]1[CH:10]=[C:2]([C:19]#[N:20])[C:3]2[CH:4]=[N:5][N:6]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:7]=2[CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Br)c2cnn(C3CCCCO3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)c2cnn(C3CCCCO3)c2c1
Temperature: 145 °C
Yield: 86 %

Procedure:
A sealed microwave vial was charged with 4-bromo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.50 g, 4.82 mmol), Zn(CN)2 (0.62 g, 5.30 mmol), Pd(PPh3)4 (0.22 g, 0.19 mmol), and DMF (13 mL). The mixture was degassed for 5 min under nitrogen and then heated in a microwave reactor at 145° C. for 25 min. The mixture was diluted with EtOAc and filtered. The filtrate was partitioned between water and EtOAc, and the layers were separated. The organic layer was washed with water (3×), dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by SiO2 chromatography to afford 6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as a solid (1.06 g, 86%). MS (ESI) m/z: 258.2 [M+1]+.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[CH:14]1([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15]1.[H-].[Na+]>CS(C)=O.C(OCC)C.[Cl-].[Na+].O>[CH:14]1([C:17]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:10][NH:11][CH:12]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)C=CC1CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)c1c[nH]cc1C1CC1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 86.1 %

Procedure:
A solution of 8.77 g of p-toluenesulphonylmethyl isocyanide and 5.67 g of methyl 3-cyclopropylacrylate in 72 mL of dimethyl sulphoxide and 145 mL of diethyl ether is added dropwise over 1.5 hours and under an argon atmosphere to a suspension of 1.73 g (54 mmol) of sodium hydride (at 75% by weight in liquid petroleum jelly) in 90 mL of diethyl ether. The reaction is exothermic. After the reaction mixture has been stirred at room temperature for 2.75 hours, 180 mL of brine are added cautiously, and the mixture is extracted twice with 100 mL of diethyl ether. The organic phase is washed with water, dried and then concentrated to dryness under reduced pressure (2.7 kPa), giving 6.39 g of 4-cyclopropyl-3-methoxycarbonyl-1H-pyrrole in the form of a yellow solid melting at 107° C.
Reaction SMILES: [N:1]1C=CC(N2CCC3(CCNCC3)C2)=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[C:31]([C:33]1[CH:48]=[CH:47][C:36]([CH2:37][CH2:38][NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=1)#[N:32].C(N)CN>>[NH:1]1[CH2:2][CH2:3][N:32]=[C:31]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH2:38][NH2:39])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Reactant: c1cc(N2CCC3(CCNCC3)C2)ccn1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: NCCN
Product: NCCc1ccc(C2=NCCN2)cc1
Temperature: 120 °C

Procedure:
Boc2O (818 mg, 3.75 mmol, 1.5 eq.) was added to a stirred solution of 2-(4-bromophenyl)ethanamine (500 mg, 2.5 mmol, 1.0 eq.) and TEA (1.5 ml, 7.5 mmol, 3.0 eq.) in DCM (25 ml) at 0° C. and resulting reaction mixture is stirred at 25° C. for 6 h. The reaction mixture was diluted with DCM (75 ml), washed with water (2×50 ml) and brine (50 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue triturated with hexanes to yield the desired product as an off white solid. Yield: 100% (750 mg, 2.5 mmol) 2. A mixture of tert-butyl 4-bromophenethylcarbamate (750 mg, 2.5 mmol, 1.0 eq.) and Zn(CN)2 (439 mg, 3.75 mmol, 1.5 eq.) in dry DMF (15 ml) was degassed with argon for 15 min. Xanthphos (290 mg, 0.5 mmol, 0.2 eq.) and Pd2(dba)3 (229 mg, 0.25 mmol, 0.1 eq.) were added to the reaction mixture and it was heated to 100° C. for 18 h. The reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with brine (50 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (neutral alumina, 10% ethyl acetate in hexanes) to yield the desired product as a reddish solid. Yield: 73% (450 mg, 1.83 mmol) 3. P2S5 (48 mg) was added to a mixture of tert-butyl 4-cyanophenethylcarbamate (450 mg, 1.83 mmol, 1.0 eq.) and freshly distilled ethylenediamine (2.4 ml, 33.85 mmol, 18.5 eq.) and the resulting reaction mixture was heated to 120° C. for 4 h. The reaction mixture was cooled to 25° C. and poured into ice-cold water (20 ml). It was then extracted with DCM (40 ml). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure to yield the desired product. Yield: 94% (500 mg, 1.73 mmol) 4. TFA (1 ml) was added to a solution of tert-butyl 4-(4,5-dihydro-1H-imidazol-2-yl)phenethylcarbamate (214 mg, 0.74 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[F:20])=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[F:20])=[S:31])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cc(C(F)(F)F)ccc1C(=S)Nc1ccc(Br)cc1
Temperature: 25 °C
Yield: 162.2 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (7.1 g, 0.0196 mol) and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (3.97 g, 0.0098 mol) was heated in toluene at reflux under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:8) as mobile phase to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzenecarbothioamide (6.0 g, 0.0159 mol) as a yellow solid.
Reaction SMILES: [Cl:1][O-].[Na+].[CH3:4][N:5]1[C:9]([CH:10]([OH:23])[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=2[Cl:22])=[CH:8][CH:7]=[N:6]1>C(O)(=O)C>[CH3:4][N:5]1[C:9]([C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=2[Cl:22])=[O:23])=[C:8]([Cl:1])[CH:7]=[N:6]1
Reactant: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2c(Cl)cnn2C)c(Cl)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.3 g of an aqueous 10 % sodium hypochlorite solution are added to a solution of 3.9 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol in acetic acid and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated to remove acetic acid, and ethyl acetate is added to the residue. The organic layer is separated, washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 2.1 g of (1-methyl-4-chloropyrazol-5-yl)-(2,3-dichloro-4,5-dimethoxyphenyl)-methanon e.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:47][CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:47][CH3:48])[N:20]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A mixture of hydroxylammonium chloride (3.8 g), sodium hydrogen carbonate (5.4 g) and dimethyl sulfoxide (26 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-2-ethyl-1-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.6 g) was added, and the mixture was stirred at 90° C. overnight. 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. The residue was dissolved in tetrahydrofuran (26 mL), N,N′-carbonyldiimidazole (1.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution 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 (2.0 g, 70%) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:37][CH2:36]3)[CH2:27][CH2:26]2)=[O:24])=[CH:11][C:10]=1[Cl:38])C.O.O.[OH-].[Li+]>O1CCOCC1>[Cl:38][C:10]1[CH:11]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:37][CH2:36]3)[CH2:27][CH2:26]2)=[O:24])[C:13]([Cl:15])=[CH:14][C:9]=1[C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[O:39]
Reactant: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 86.3 %

Procedure:
To a solution of 0.85 g (1.46 mmol) 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic acid ethyl ester (Example 33) in 7.5 mL dioxane were added 7.5 mL water and 0.076 g (1.81 mmol) lithium hydroxide monohydrate. The resulting suspension was stirred for 2.25 hours at room temperature and dioxane was removed by evaporation. The pH of the solution was adjusted to 2.5 by adding 1.9 mL 1M aqueous hydrochloric acid and the suspension was stirred for 2 hours at room temperature. The suspension was filtered, the filter cake washed with water and dried under high vacuum to give 0.70 g (86%) of the desired compound as an off-white solid. MS (ESI): m/z=555.12 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15](O)[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:8]=1)[CH3:2].C(N(S(F)(F)[F:38])CC)C.O>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@@H:15]([F:38])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:8]=1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)[C@H](Cc1cccc(OC[C@H](O)COc2ccc(Cl)cc2Cl)c1)OC(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccc(OC[C@@H](F)COc2ccc(Cl)cc2Cl)c1)OC(C)C
Temperature: -78 °C
Reaction time: 48 h

Procedure:
Using 174 mg of 3-{3-[3-(2,4-dichlorophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid ethyl ester (Production example 279e) was dissolved in 5 ml of dichloromethane, and the mixture was cooled to −78° C. To the solution was added 0.15 ml (diethylamino) sulfur trifluoride, and stirring was continued at room temperature for 2 days. Water was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed. The residue was purified by silica gel column chromatography, to give 79 mg of 3-{3-[3-(2,4-dichlorophenoxy)-2 (R)-fluoropropoxy]phenyl}-2(S)-isopropoxypropanoic acid ethyl ester in the 7:1→5:1 hexane-ethyl acetate fraction. This product was dissolved in 4 ml of ethanol and 0.5 ml of tetrahydrofuran and 0.5 ml of 1N lithium hydroxide were added, and stirring was continued overnight at room temperature. The solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed. The residue was purified by silica gel column chromatography, to give 61 mg of the title compound in the 3:1→1:1 hexane-ethyl acetate fraction.
Reaction SMILES: Cl.C(O[CH:5](OCC)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Br:17])[CH:10]=1)C.[C:21]([S-:23])#[N:22].[K+]>O.C(O)C.Cl>[Br:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH2:8][N:7]1[CH:6]=[CH:5][N:22]=[C:21]1[SH:23]
Reactant: N#C[S-]
Reactant: CCOC(CNCc1ccc(OC)c(Br)c1)OCC
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2ccnc2S)cc1Br

Procedure:
A solution of 10.74 g (0.029 mole) of N-(3-bromo-4-methoxybenzyl)aminoacetaldehyde diethyl acetal hydrochloride and 3.37 g (0.35 mole) of KSCN in 50 ml of H2O, 50 ml of ethanol and 5 ml of 3N HCl was refluxed for 4.5 hr. One hundred ml of H2O was added and the mixture was cooled. A solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-(3-bromo-4-methoxybenzyl)-2-mercaptoimidazole, 6.3 g (72%), mp 188°.