Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:28][CH:29]1[CH2:31][CH2:30]1>[F-].[K+]>[I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2
Reactant: OCC1CC1
Agent: [F-]
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2

Procedure:
4.65 g (10 mmol) of tert.butyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylate, 24 g (330 mmol) of hydroxymethyl-cyclopropane and 3 g (13 mmol) of tetraethyl crthotitanate are stirred at 115° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate and hexane there is obtained cyclopropylmethyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 164°-165°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28])#[N:23].O1CCCC1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:22]#[N:23])[CH:25]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C#N)c4)c3)cc2s1
Yield: 55.5 %

Procedure:
Using N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-cyanobenzoic acid (157 mg, 1.07 mmol), tetrahydrofuran (4 mL), N,N-dimethylformamide (10 μL), oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (4 mL), and in the same manner as in Example A40(xi), the title compound (127 mg, 55%) was obtained as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].I[CH2:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH3:12]
Reactant: CCI
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 2-Bromo-4-chlorophenol (2.12 g, 10.2 mmol) in 25 mL acetone was added iodoethane (0.850 mL, 10.6 mmol) and cesium carbonate (4.08 g, 12.5 mmol). The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated to yield 2.37 g (98%) of 2-bromo-4-chloro-1-ethoxybenzene as a yellow oil, which was carried forward without further purification. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: 7.67 (d, J=2.6, 1H), 7.39 (dd, J=8.8, 2.6, 1H), 7.12 (d, J=8.9, 1H), 4.11 (q, J=7.0, 2H), 1.35 (t, J=7.0, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:30])=O>O1CCOCC1.C(#N)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([CH2:26][Cl:30])=[CH:22][CH:21]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCc1ccc(-c2cc3c(Nc4ccc5c(c4)OCO5)ncnc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: ClCc1ccc(-c2cc3c(Nc4ccc5c(c4)OCO5)ncnc3[nH]2)cc1
Reaction time: 16 h

Procedure:
To a suspension of 1.83 g of {4-[4-(benzo[1,3]dioxol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol in 56 ml of dioxane/acetonitrile 1:1 under N2-atmosphere, 3.1 ml of thionylchloride are added. After 16 h stirring, the suspension is diluted with ethyl acetate and NaHCO3-solution. The aqueous layer is separated off and extracted twice with ethyl acetate. The organic phases are washed with water and brine, dried (MgSO4) and concentrated to yield the title compound; MS-ES+: (M+H)+=379; HPLC (conditions see Examples 67-78) tR=11.4 min.
Reaction SMILES: O.[NH2:2][NH2:3].[IH:4].[CH2:5]([NH:12][C:13](=[N:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)SC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[IH:4].[NH2:2][NH:3][C:13]([NH:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(=NCc1ccccc1)NCc1ccccc1
Reactant: NN
Agent: I
Solvent: CCO
Solvent: O
Product: NNC(=NCc1ccccc1)NCc1ccccc1

Procedure:
A solution of 6 ml. of hydrazine hydrate and the solution of 1,3-dibenzyl-2-methylthiopseudourea hydroiodide from Example 13 in 500 ml. of absolute ethanol is heated at reflux for 4 hours and then evaporated to dryness under reduced pressure. The residual solid is crystallized from isopropyl alcohol twice giving the desired product as colorless crystals, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:35][CH3:36])=[C:16]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]([CH2:32][CH2:33][OH:34])[CH3:31])=[O:29])[CH:23]=4)[C:17]([CH3:21])=[C:18](Cl)[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:37][N:38](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:35][CH3:36])=[C:16]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]([CH2:32][CH2:33][OH:34])[CH3:31])=[O:29])[CH:23]=4)[C:17]([CH3:21])=[C:18]([C:37]#[N:38])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)N(C)CCO)c1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C#N)c(C)c1-c1ccnc(C(=O)N(C)CCO)c1
Temperature: 120 °C

Procedure:
The above catalyst (0.05 mL) was added to a mixture of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide (from Example 19) (4.0 mg, 0.0078 mmol), zinc (0.22 mg, 0.0034 mmol) and zinc cyanide (0.92 mg, 0.0078 mmol) in N,N-dimethylacetamide (0.1 mL). The mixture was degassed and then the reaction was heated at 120° C. for 1.5 hours. The crude mixture was applied on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C26H29N8O3 (M+H)+: m/z=501.2; Found: 501.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[C:9]=1[OH:10])[C:5]#[N:6].[N:12]([O-:14])=[O:13].[Na+].BrBr.O>C(O)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[OH:10])[C:5]#[N:6]
Reactant: O=N[O-]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
(I1B): To a suspension of 3,5-dibromo-4-hydroxybenzonitrile (2.11 g, 7.62 mmol) in acetic acid (70 mL) was added sodium nitrite (2.63 g, 38.1 mmol) in small portion, evolving bubbles and bromine were observed. After addition, the mixture was stirred at 50° C. overnight. Reaction was cooled to room temperature; water (250 ml) was added and extracted with EtOAc for two times. The combined extracts were washed with water and brine, dried over MgSO4 filtered and the filtrate was concentrated to give yellow orange solid. The solid was treated with small amount of MeOH, collected by filtration, rinsed with MeOH, dried to afford 1.56 g of 3-bromo-4-hydroxy-5-nitrobenzonitrile as yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3C3C=CC=C(OC)C=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:41][OH:42].O>C(#N)C>[CH:6]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:1]3[CH:13]=[CH:5][C:41]([O:42][CH2:7][CH2:6][CH3:11])=[CH:3][CH:2]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: COc1cccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Solvent: O
Solvent: CC#N
Product: CCCOc1ccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1

Procedure:
(830 mg, 57%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-4-propoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 7.83-7.59 (m, 3H), 7.54-7.12 (m, 11H), 6.93 (d, J=8.5 Hz, 2H), 5.43-5.12 (m, 1H), 4.71-4.53 (m, 1H), 4.29-4.05 (m, 3H), 3.88 (t, J=6.4 Hz, 2H), 3.63-3.41 (m, 2H), 1.79 (sxt, J=7.0 Hz, 2H), 1.09-0.98 (m, 3H); [α]20D −7.54° (3.05 mg/mL, MeOH). LCMS retention time=1.952 min., m/z=561 (M+H), 99.1% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[NH:38][C:37]1=[O:45].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[NH:38][C:37]4=[O:45])[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccccc2n1CCCI
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Yield: 72.7 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.823 g, 1.92 mmol), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.58 g, 1.92 mmol), and potassium carbonate (0.39 g, 2.88 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as a white solid (0.84 g, 73%); 1H NMR (DMSO-d6); δ 0.93-0.96 (m, 1H); 1.14-1.25 (m, 4H); 1.52 (s, 9H); 1.57-1.62 (m, 9H); 1.79 (m, 2H); 2.29-2.36 (m, 4H); 2.63 (m, 3H); 3.82 (t, J=6.8 Hz, 2H); 4.08 (s, 2H); 4.43 (s, 2H); 6.97-7.01 (m, 3H); 7.14 (d, J=6.4 Hz, 1H); 7.44-7.49 (m, 2H); 7.72 (s, 1H); 7.81 (dt, J=2.4 Hz and 6.4 Hz, 1H); 10.8 (s, 1H); MS for C35H47N5O4 m/z 602 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:30][O:31][CH:32](OC)[N:33](C)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:27])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][C:32]([O:31][CH3:30])=[NH:33])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Solvent: C1CCOC1
Product: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(=N)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
In a solution of 0.09 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methoxymethyl benzoic acid amide in 2 mL of tetrahydrofuran, 0.05 g of N,N-dimethylformamide dimethylacetal was added, and stirred at room temperature for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 2 mL of tetrahydrofuran, a solution of 0.02 g of methoxyamine hydrochloride in 2 mL of water was added dropwise. After the completion of the addition dropwise, it was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, 5 mL of water was added in the residue, and extracted with ethyl acetate (10 mL×1). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:4) to obtain 0.07 g of the aimed product as white crystal.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[N:10]=[C:9]([C:27]#[N:28])[C:8]=2[N:7]=[CH:6]1.CN(C)C=O.[OH-].[Li+].Cl>O>[C:27]([C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:4][C:3]([OH:29])=[O:2])[C:13]=2[CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[N:10]=1)#[N:28]
Reactant: CCOc1ccc(-c2cc3c(ncn3CC(=O)OC)c(C#N)n2)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2cc3c(ncn3CC(=O)O)c(C#N)n2)cc1C(F)(F)F
Yield: 94.9 %

Procedure:
To a solution of [4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]-pyridin-1-yl]-acetic acid methyl ester (110 mg, 0.27 mmol) in a 1:1 mixture of dimethylformamide (2 ml) and water (2 ml) was added lithium hydroxide (19 mg, 0.81 mmol) dissolved in 200 μL of water. An additional 2 ml of dimethylformamide was added to aid solubility. The mixture was stirred at room temperature for 30 minutes before acidification to pH 1 with 2N HCl solution and filtration. The solid obtained was washed with ether before dissolving in acetone and concentration under reduced pressure to remove residual organic solvents and afford [4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-imidazo[4,5-c]pyridin-1-yl]-acetic acid (100 mg). 1H NMR (DMSO): δ 8.76 (s, 1H) 8.64 (s, 1H) 8.37 (m, 3H) 7.43 (d, 1H) 5.31 (s, 2H) 4.27 (q, 2H) 1.38 (t, 3H); MS m/z 391.7 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:3]([CH3:4])([CH3:8])[CH3:1])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(CC(=O)O)ccc1F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reaction time: 12 h
Yield: 106.5 %

Procedure:
2-(3-Cyano-4-fluorophenyl)acetic acid (14.3 g, 79.8 mmol) was diluted with THF (150 mL) followed by the addition of tert-butyl N,N′-diispropylcarbamimidate (48.0 g, 239 mmol). After stirring for 12 hours, the reaction was filtered and the filtrate was concentrated. The residue was taken up in ethyl acetate 100 mL and washed with 1N HCl saturated bicarbonate water and brine. The organic layer was dried over MgSO4, filtered and concentrated. Additional precipitate was removed by filtration. The remaining residue was purified on a Biotage 40M column eluting over silica gel with hexanes:ethyl acetate (9:1) to yield tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (10.0 g, 53.3% yield) as a clear oil that later solidified to a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].CS(O[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:22][N:21]=1)(=O)=O.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][N:21]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COS(C)(=O)=O)nc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 12 %

Procedure:
A solution of 4-(methanesulfonyl)phenol (25 mg, 0.14 mmol) in dry tetrahydrofuran (0.5 mL) was added dropwise over 5 minutes to an ice-cooled suspension of sodium hydride (55% dispersion in mineral oil, 10 mg, 0.22 mmol) in dry tetrahydrofuran (0.5 mL). After stirring for an additional 20 minutes under N2, a solution of tert-butyl 4-[2-(methanesulfonyloxymethyl)pyridine-5-yl]piperidine-1-carboxylate (59 mg, 0.16 mmol) in dry tetrahydrofuran (0.5 mL) was added dropwise over 5 minutes to the mixture. The resulting mixture was stirred at room temperature for 2 hours and then refluxed overnight, to which was added saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give a white solid. The solid was dissolved in ethyl acetate and extracted with 1N hydrochloric acid. The aqueous layer was neutralized by adding 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a white crystal (7.5 mg, yield 11%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][C:14]#[CH:15]>>[C:16]1([CH2:12][CH2:13][C:14]#[C:15][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: C#CCCc1ccccc1
Product: C(#Cc1ccc2ccccc2n1)CCc1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-chloroquinoline (300 mg, 1.83 mmol) and 1-(but-3-ynyl)benzene (200 mg, 1.54 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 148 mg (0.57 mmol, 37%) of 2-(4-phenylbut-1-ynyl)quinoline as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]([O:7][CH2:8][CH3:9])=[CH:5][S:4][CH:3]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[CH:13][NH:1][C:2]1[C:6]([O:7][CH2:8][CH3:9])=[CH:5][S:4][CH:3]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: CCOc1cscc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cscc1OCC)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of 3-amino-4-ethoxythiophene (10 g) and diethyl ethoxymethylenemalonate (15.1 g) was stirred at 95° in an apparatus set for distillation. When ethanol evolution ceased (3 hours) the mixture was cooled to ambient temperature and the semi-solid was triturated with boiling petroleum ether (b.p. 60°-80°, 50 ml) then the mixture diluted with more petroleum ether (b.p. 60°-80, 300 ml). The solid was collected, washed with petroleum ether (b.p. 60°-80°) and dried to give the novel compound diethyl[(4-ethoxy-3-thienyl)amino]methylenemalonate, m.p. 108°-109°.
Reaction SMILES: [CH3:1][CH:2]([S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:18](Br)[C:19]#[CH:20]>>[CH3:1][CH:2]([S:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:20][C:19]#[CH:18])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)Sc1ccc(CO)cc1
Reactant: C#CCBr
Product: C#CCOCc1ccc(SC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 26, by reacting p-[(1.5-dimethylhexyl)thio]benzyl alcohol with propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)thio]-α-propargyloxy-toluene; nD29 = 1.5243.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[I:14]I>C1COCC1>[F:6][C:7]1[C:12]([I:14])=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1
Reactant: Cc1ccc(F)nc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cnc(F)c(I)c1
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A solution of dilsopropylamine (7.0 mL, 50.0 mmol) in THF (100 mL) at −78° C. was treated with 2.5M n-butyllithium in hexanes (20 mL, 50.0 mmol), stirred for 15 minutes, treated dropwise with a solution of 2-fluoro-5-methylpyridine (5.55 g, 50.0 mmol) in THF (20.0 mL), stirred for 4 hours, treated slowly with a solution of iodine (12.7 g. 50.0 mmol) in THF (50 mL), quenched with water, and extracted with diethyl ether. The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/diethyl ether to provide 7.24 g (61%) of 2-fluoro-3-iodo-5-methylpyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([C:7]([C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:17][CH2:18]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 2 h

Procedure:
A solution of 17.4 g. (0.075 mol.) of 3,4 dinitrobenzoylchloride in 250 ml of methylene chloride is treated at 0°-20° C. with a solution of 13 g. (0.15 mol.) of morpholine in 100 ml. of methylene chloride. The solution is kept at 20°-25° C. for 2 hrs., the solvent is evaporated and the residue triturated with water. Recrystallization from methanol affords 4-morpholinocarbonyl-1,2-dinitrobenzene (m.p. 136°-137° C.). 17.0 G. of 4-morpholinocarbonyl-1,2-dinitrobenzene in 340 ml. of methanol is hydrogenated for 3 hrs. at 45-50 psi in the presence of 1.7 g of 5% palladized charcoal. The resulting solution of 1,2-diamino-4-morpholinocarbonylbenzene is filtered and concentrated to ~170 ml. 14.0 G. of 1,3-bis-methoxycarbonyl-S-methyl isothiourea, 170 ml. of water and 4 ml. of acetic acid are added to the diamine solution and the mixture is refluxed for 3 hrs. The solution is concentrated and cooled. Filtration and recrystallization from methanol-chloroform affords 5(6)-morpholinocarbonyl-2-carbomethoxyaminobenzimidazole (m.p. 224° C. dec.).