Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:54][O:55][CH2:56][C@H:57](O)[CH3:58]>ClC>[CH3:54][O:55][CH2:56][C@@H:57]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:58]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2C)c1
Reactant: COC[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC[C@H](C)Oc1cc(OCc2ccccc2C)cc(C(=O)OC)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A stirred suspension of methyl 3-hydroxy-5-{[(2-methylphenyl)methyl]oxy}benzoate (15.3 g, 56.25 mmol) and triphenyl phosphine (14.4 g, 55 mmol) in dry chloromethane (900 ml) was cooled in an ice-bath and diisopropyl azodicarboxylate (11.88 ml, 55 mmol) was added dropwise. The reaction mixture was stirred at 0-5° C. for 30 minutes and (R)-methoxy-propan-2-ol was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours, and filtered through diatomaceous earth. The filtrate was evaporated and purified by column chromatograph on silica gel eluting with 10% ethyl acetate in iso-hexane to give the desired compound (10.7 g, 55%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][O:16]S(C(F)(F)F)(=O)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:24][C:25]1[C:29]([CH3:30])=[C:28]([CH3:31])[N:27]([CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]2)[N:26]=1.C(N(CC)CC)C.O.C(Cl)[Cl:49]>>[Cl:49][C:10]1[CH:9]=[N:8][C:13]([CH3:14])=[C:12]([CH:11]=1)[C:15]([NH:39][C@H:36]1[CH2:35][CH2:34][C@H:33]([CH2:32][N:27]2[C:28]([CH3:31])=[C:29]([CH3:30])[C:25]([CH3:24])=[N:26]2)[CH2:38][CH2:37]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1nn(C[C@H]2CC[C@H](N)CC2)c(C)c1C
Reactant: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](Cn2nc(C)c(C)c2C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 5-chloro-2-methylnicotinoyl chloride (Ex. 17 step 1) and trans-4-(3,4,5-trimethyl-pyrazol-1-ylmethyl)-cyclohexylamine (step 3) (197 mg, ca. 0.67 mmol) in dry DCM (6.5 mL) is added triethylamine (0.37 mL, 2.68 mmol). The mixture is stirred at room temp for 45 minutes. Water (20 mL) is added and the mixture is extracted with EtOAc (3×20 mL). The EtOAc extracts are combined, washed with saturated brine (20 mL), dried (MgSO4), filtered and evaporated to give a pale yellow gum. The mixture is purified by chromatography on silica gel eluting with 0-100% EtOAc to give a colourless solid which was triturated with Et2O to afford the title product. MS m/z 375.3/377.3 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 8.54 (1H, d), 8.39 (1H, d), 7.79 (1H, d), 3.74 (2H, d), 3.67 (1H, m), 2.47 (3H, s), 2.10 (3H, s), 2.02 (3H, s), 1.88 (2H, m), 1.83 (3H, m), 1.70 (1H, m), 1.57 (2H, m), 1.14 (4H, m).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20]([OH:22])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C.Cl.[NH2:57][C@H:58]([C:74]([O:76][CH3:77])=[O:75])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:62][CH:61]=1>CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:20]([NH:57][C@H:58]([C:74]([O:76][CH3:77])=[O:75])[CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)=[CH:64][CH:65]=1)=[O:22])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 169.3 %

Procedure:
Dipeptide Boc-Arg(Tos)-Tyr(Bzl)-OCH3 : A solution of Boc-Arg(Tos)-OH (2.14 g, 5 mmol) and DPPA (1.37 g, 5 mmol) in DMF (100 mL) was cooled to -5° C. DIEA (2.6 mL, 15 mmol) and HCl.H-Tyr(Bzl)-OCH3 (1.44 g, 4.5 mmol) were added, each in one portion, to the cooled solution. The solution was stirred at -10° C. for 2h, allowed to stand at 4° C. for 18h, and then evaporated to dryness. The residue was dissolved in EtOAc (75 mL). The solution was washed sequentially with H2O, 1N HCl, 5% aqueous NaHCO3 and H2O, dried, and evaporated to dryness. The residue was dissolved in EtOAc. Addition of Et2O caused an oil to separate from the solution. The mixture was cooled (0° C.) and triturated. The solvent phase of the mixture was removed by decantation. Et2O was added to the residue. After warming the mixture, the preceding trituration and decantation treatment was repeated. Finally, the product was dried under reduced pressure to yield Boc-Arg(Tos)-Tyr(Bzl)-OCH3 (5.3 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.CC(=O)[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: ClCCCc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1ccccc1CCCCl

Procedure:
A mixture of 258 g (1.27 mol) of 2-(3-chloropropyl)benzyl chloride, 2, 140 g (1.4 mol) of 2,4-pentanedione, 6, 175 g (1.27 mol) potassium carbonate, and 700 ml of absolute ethanol was stirred at reflux for 18 hours. Evaporation of the alcohol gave a residue which was partitioned between ether and water. The organic phase was dried over anhydrous MgSO4, concentrated and the residue distilled to give the chloro ketone 7, 218 g, bp 123°-127° C/0.2 mm.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:53][C:54]([NH2:58])([CH3:57])[CH2:55][NH2:56]>CN(C=O)C>[NH2:58][C:54]([CH3:57])([CH3:53])[CH2:55][NH:56][C:16]([C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])[C:7]2=[N:14][C:13]=1[CH3:15])=[O:18]
Reactant: CC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.31 mmol), 151 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.47 mmol) and 127 mg of 4-methylmorpholine (1.26 mmol) were initially charged in 2 ml of DMF. 55 mg of 2-methylpropane-1,2-diamine (0.63 mmol) were then added, and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The crude product was taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulphate. The mixture was then filtered and the filtrate was concentrated and lyophilized. This gave 80 mg of the title compound (66% of theory).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][CH:13]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:14][CH:15]=[CH2:16])=[CH:10][CH:9]=1.B.CSC.C1C[O:34]CC1>CCOCC>[OH:34][CH2:16][CH2:15][CH2:14][CH:13]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[O:12][C:11]1[CH:25]=[CH:26][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1
Reactant: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Reactant: C1CCOC1
Agent: B
Solvent: CSC
Solvent: CCOCC
Product: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
4-{1-[4-(Tetrahydro-2H-pyran-2-yloxy)phenoxy]-3-butenyl}benzonitrile (4.6 g, 13 mmol; from step (d) above) was dissolved in dry THF (50 mL) under argon and cooled to −5° C. Borane-methylsulfide complex (BH3×SMe2) (3.5 mL of a 2 M solution in ether) was added dropwise at 0 to 5° C. The mixture was stirred at that temperature for 1.5 h. After 4 h at rt, tlc showed that the reaction was complete. The reaction mixture was quenched with 14 mL of H2O and 5 g of NaBO3. The mixture was stirred overnight, the solvent decanted off, and the residue treated with ether and decanted. The combined organic fractions were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by chromatography on silica (iso-propanol:ethyl acetate:heptane; 5:20:70). Yield: 2.44 g (58%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][O:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)CCCc1ccc(CCO)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCc1ccc(CCOc2ncnc3ccccc23)cc1
Reaction time: 3.5 h
Yield: 42.6 %

Procedure:
A dry 50 mL flask was fitted with an addition funnel. To the flask were added 4-chloroquinazoline (592 mg, 3.6 mmol), anhydrous tetrahydrofuran (10 mL), and 60 wt % sodium hydride (187 mg, 4.7 mmol). A solution of Example 1B (800 mg, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise using the addition funnel. The reaction was stirred for 3.5 hours. The reaction was diluted with ethyl acetate and quenched by the addition of aqueous 0.1 N hydrochloric acid. The mixture was transferred to a separatory funnel and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Column chromatography [silica gel; eluent hexanes-ethyl acetate (4:1)] provided the desired product (538 mg, 43%). 1H (CDCl3) δ ppm): 1.92-1.98 (m, 2H); 2.33 (t, 2H); 2.64 (t, 2H); 3.19 (t, 2H); 3.66 (s, 3H); 4.79 (t, 2H); 7.15 (d, 2H); 7.27 (d, 2H); 7.57 (t, 1H); 7.83 (t, 1H); 7.94 (d, 1H); 8.15 (d, 1H); 8.80 (s, 1H). 26.68, 33.59, 34.93, 35.03, 51.67, 67.89, 116.48, 123.72, 127.23, 127.82, 128.87, 129.24, 133.74, 135.76, 139.90, 151.08, 154.56, 166.89, 174.10.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]([OH:7])([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccccc1
Reactant: CC(C)c1ccccc1
Product: CC(C)(O)c1ccccc1

Procedure:
From the synthesis of phenol by oxidation of cumene, a crude oxidate containing, after concentration, essentially cumenyl hydroperoxide (CHPO) and 2-phenyl-2-propanol was obtained.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:32])[NH:11][C@:12]([CH2:30][OH:31])([CH3:29])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.Cl>C(#N)C.CCOC(C)=O>[C:5]([O:9][C:10]([N:11]1[C:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:20]=2)([CH3:29])[CH2:30][O:31][S@:1]1=[O:2])=[O:32])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCCCCCCOc1ccc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CCC2(C)CO[S@@](=O)N2C(=O)OC(C)(C)C)cc1
Temperature: -10 °C

Procedure:
A stirred solution of thionyl chloride (0.14 ml, 1.91 mMol) in acetonitril (10 ml) is cooled to −40° C. At this temperature, a solution of [(R)-3-(4-heptyloxy-phenyl)-1-hydroxymethyl-1-methyl-propyl]-carbamic acid tert-butyl ester (300 mg, 0.76 mMol) in acetonitril (5 ml), and pyridine (0.31 ml, 3.81 mMol) are added successively. The mixture is allowed to warm to −10° C. over 2.5 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and HCl (aqueous, 1 M). The aqueous phase is extracted twice with AcOEt. The combined organic layers are washed with NaHCO3 (saturated aqueous solution), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 5%→15% AcOEt in heptane gives the title compounds as colourless oils (2 diastereomers, dr=1:1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A stirred solution of 2.5 g of diethylamine and 3.5 g of triethylamine in 30 ml of methylene chloride was cooled in an ice bath while 4.9 g of benzoyl chloride was added dropwise. The cooling bath was removed and the mixture stirred at ambient temperature for 18 hours. The insolubles were removed by filtration followed by methylene chloride washing. The combined filtrates were washed with water and brine, dried and evaporated to a yellow oil which was distilled in a Kugelrohr still to give 5.91 g of the desired product as a colorless oil, 70°/300 mm.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1.C1C(=O)N(Br)C(=O)C1.C1CCN2C(=NCCC2)CC1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1
Reactant: O=C1CCc2c(-c3ccccc3Cl)cc(Cl)nc2N1c1ccccc1Cl
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1ccc2c(-c3ccccc3Cl)cc(Cl)nc2n1-c1ccccc1Cl
Reaction time: 2 h
Yield: 69 %

Procedure:
7-Chloro-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,8]naphthyridin-2(1H)-one (220 mg, 0.545 mmol) in carbon tetrachloride (3 ml) was treated with NBS (110 mg; 0.618 mmol) and AlBN (1 mg) and heated under reflux for 1 h. Further NBS (110 mg, 0.618 mmol) and AlBN (2 mg) were added and heating under reflux continued for a further 2 h. DBU (0.2 ml) was added, the mixture cooled, filtered, and further carbon tetrachloride (3 ml) added, followed by 2M hydrochloric acid (3 ml). The mixture was purified by column chromatography over silica (20 g) eluting with cyclohexane-ethyl acetate (100:0-60:40) to afford the title compound as a white solid (151 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.CO.[NH3:20]>>[NH2:20][CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[OH:9]
Reactant: N
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Solvent: CO
Product: NCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Temperature: 130 °C

Procedure:
2-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (500 mg, 1.40 mmol) was dissolved in 2M NH3 in methanol (5 ml, 10.0 mmol) and the solution was heated in a microwave at 130° C. for 60 minutes. Upon cooling, the solvent was removed in vacuo to furnish the desired product. Three identical reactions were carried out and afforded 1.55 g (98%) of the product 2-amino-1-(4-chloro-phenyl)-1-[4-iodo-phenyl]-ethanol. The crude product was pure and was used in the next step without purification.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:8][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)/[CH:4]=[CH:5]\[CH2:6][CH3:7]>CC(C)=O>[I-:2].[CH2:3]([O:8][C:9]1[C:13]([C:14]2[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)/[CH:4]=[CH:5]\[CH2:6][CH3:7]
Reactant: CI
Reactant: CC/C=C\COc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CC/C=C\COc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and cis-3-(3-(2-pentenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.53 g (46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].C(N(CC)CC)C.[CH:25]([NH:28][C:29]([CH:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32])=[O:30])([CH3:27])[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:36]1[CH2:35][CH2:34][N:33]([CH:31]([C:29]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:30])[CH3:32])[CH2:38][CH2:37]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CC(C)NC(=O)C(C)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC(C)C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.15 g of 3,4,5-trimethoxycinnamoyl chloride and 8.92 ml of triethylamine are added with ice cooling and stirring to a solution of 9.80 g of 1-[1-(isopropylaminocarbonyl)ethyl]piperazine in 200 ml of chloroform, and the resulting solution is stirred at room temperature for 1 hour.
Reaction SMILES: B(F)(F)F.CC[O:7][CH2:8][CH3:9].[Cl:10][C:11]1[N:16]=[CH:15][C:14](N)=[C:13]([I:18])[CH:12]=1.N(OC(C)(C)C)=[O:20]>COCCOC.C(Cl)Cl>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([O:7][C:8](=[O:20])[CH3:9])=[C:13]([I:18])[CH:12]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: CC(C)(C)ON=O
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)Oc1cnc(Cl)cc1I
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 49 %

Procedure:
Boron trifluoride diethyl etherate (6.2 mL, 48.9 mmol) was slowly added to a cooled −15° C. solution of 6-chloro-4-iodo-pyridin-3-ylamine (5.82 g, 22.9 mmol) dissolved in DME (36 mL) and CH2Cl2 (12 mL). Tert-butyl nitrite (3.6 mL, 27.6 mmol) was slowly added maintaining the temperature below −5° C. The reaction was stirred at −10° C. for 25 minutes and then at 0° C. for 20 minutes. The mixture was diluted with pentanes (100 mL) and the tetrafluoroborate diazonium salt was collected by filtration. The salt was dissolved immediately by dissolving it in acetic anhydride (20 mL) and heated to 95° C. for 2 hours. The reaction was cooled to room temperature and partitioned between diethyl ether and saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the product as a white solid (3.34 g, 49%). 1H NMR (300 MHz, CDCl3): δ 2.40 (s, 3H), 7.82 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]([NH2:21])=[O:26])[C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([CH3:18])[CH:14]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1csc(C(=O)C2C(=O)Nc3ccc(Cl)nc32)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)nc32)c1

Procedure:
The title compound was prepared from 5-chloro-3-(4-methyl-2-thenoyl)-4-azaoxindole (Example 30) according to the procedure of Example 2C, using 5-chloro-3-(4-methyl-2-thenoyl)-4-azaoxindole (0.90 g, 3.07 mmol), N-chlorosulfonyl isocyanate (0.40 mL, 4.60 mmol), and acetonitrile (15 mL). The crude N-chlorosulfonyl isocyanate was hydrolyzed by stirring in DMSO in a flask open to the air. The product was isolated by dilution with water and filtration, and was recrystallized from acetic acid. Yield: 190 mg (18%). M.P. 227°-228° C.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][C:13]1[C:18]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:5])C.C(OC([N:30]=[C:31]=[S:32])=O)C>>[CH2:23]([O:22][CH2:21][CH2:20][O:19][C:18]1[C:13]([CH2:12][N:11]2[C:10]3[CH:9]=[CH:8][NH:7][C:6]=3[C:4](=[O:5])[NH:30][C:31]2=[S:32])=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCOC(=O)N=C=S
Reactant: CCOCCOc1cccnc1CNc1cc[nH]c1C(=O)OCC
Product: CCOCCOc1cccnc1Cn1c(=S)[nH]c(=O)c2[nH]ccc21
Yield: 28.3 %

Procedure:
The title compound (0.051 g, 28%) was prepared in accordance with general method B using 3-({[3-(2-ethoxyethoxy)pyridin-2-yl]methyl}amino)-1H-pyrrole-2-carboxylic acid ethyl ester (0.17 g, 0.52 mmol) and ethoxycarbonyl isothiocyanate (0.07 mL, 0.62 mmol).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)#[N:26]>C(#N)C>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:36]1[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][O:30][C:29]2[CH:39]=[CH:40][CH:41]=[C:27]([C:25]#[N:26])[CH:28]=2)[CH2:38][CH2:37]1)#[N:2]
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCI)c1sccc1C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1sccc1C#N
Reaction time: 72 h

Procedure:
In 1.5 ml of acetonitrile was dissolved 111 mg (0.31 mmol) of 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl iodide. To the mixture were added 56.2 μl (0.40 mmol) of triethylamine and 109 mg (0.47 mmol) of 1-(3-cyanophenoxyethyl)piperazine, followed by stirring for 3 days. The organic layer separated by adding ethyl acetate and brine to the reaction solution was dried over magnesium sulfate, and then evaporated, to give a crude product. The crude product was subjected to 12.5 g of Cromatorex NH silica gel (ethyl acetate/hexane-1/2), to give 144 mg (quantitative) of the title compound as a yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[CH3:9][S-:10].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:9][S:10][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C[S-]
Reactant: Clc1ccc(Cl)cc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CSc1ccc(Cl)cc1

Procedure:
A 4-necked, 1-liter flask equipped with a stirrer, a thermometer and a condenser tube was charged with 147.0 g (1.00 mole) of 1,4-dichlorobenzene and 67.9 g (0.10 mole) of an aqueous solution of 50 wt % tetra-n-butylphosphonium bromide. 233.6 g (1.00 mole) of an aqueous solution of 30 wt % sodium thiomethoxide was added dropwise at 80° C. over a period of 6 hours. After addition, the mixture was reacted at the same temperature for 10 hours. After completion of reaction, 157.4 g of a crude 1-methylthio-4-chlorobenzene was obtained by separation procedure.