Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:70]([NH2:74])[CH:71]([CH3:73])[CH3:72]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:74][CH2:70][CH:71]([CH3:73])[CH3:72])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NCC(C)C)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and isobutylamine (110.0 uL, 0.11 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (12.6 mg, 44%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH:20]([O:23]C3CCCCO3)[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)NC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CNC(=O)NC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 86.2 %

Procedure:
A solution of 1-{2-(3,4-dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionyl}-3-methyl-urea (150.7 mg, 0.33 mmol) in ethanol (3.4 mL) was treated with pyridinium p-toluenesulfonate (8.54 mg, 0.03 mmol). The reaction mixture was heated to 60° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230400 mesh, 80/20 methylene chloride/methanol) afforded 1-[2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionyl]-3-methyl-urea (102.2 mg, 83.7%) as a white solid: mp 82–84° C.; FAB-HRMS m/e calcd for C16H20Cl2N2O3 (M+H)+ 359.0929, found 359.0936.
Reaction SMILES: OO.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:12])=[N:8][C:9]=1[CH2:10][CH3:11].C(Cl)Cl.[OH-:16].[Na+].[OH:18]S(O)(=O)=O>>[Br:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]([N+:12]([O-:18])=[O:16])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: CCc1nc(N)ccc1Br
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52 %

Procedure:
A 0° C. solution of H2SO4 (11 mL, 10.83 mmol) was treated slowly with 30% hydrogen peroxide (5.5 mL, 9.42 mmol) in an open flask, stirred for 5 minutes, treated drop-wise with a solution of 5-bromo-6-ethylpyridin-2-amine (3.83 g, 19.05 mmol) in H2SO4 (11 mL) and stirred overnight as the cooling bath expired. The solution was poured into ice water, treated with DCM, cooled in an ice bath and treated slowly with 50% NaOH until pH˜9. The layers were separated, the aqueous layer extracted with DCM (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-bromo-2-ethyl-6-nitropyridine (2.31 g, 52%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J=8.5 Hz, 1H), 8.04-8.03 (m, 1H), 2.96 (q, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 233.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([O:24]C)=[O:23])[CH:4]=1)#[N:2].[OH-].[K+]>O.CO>[C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=[O:23])[CH:4]=1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Yield: 84.2 %

Procedure:
8.8 g of methyl 3-cyanoandrosta-3,5-diene-17β-carboxylate [prepared as described in step (a) above] and 4.3 g of potassium hydroxide were dissolved in a mixture of 20 ml of water and 200 ml of methanol, and the resulting solution was heated under reflux for 10 hours. At the end of this time, the methanol in the reaction mixture was removed by distillation under reduced pressure, the mixture was made acidic by the addition of dilute aqueous hydrochloric acid and extracted three times with methylene chloride. The organic extract was washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 150 g of silica gel using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 16:84 by volume as the eluent, to give 7.1 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O.C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=3[F:18])[CH:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)n2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNc2nccc(Oc3ccc([N+](=O)[O-])cc3F)n2)cc1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 2-chloro-4-(2-fluoro-4-nitrophenoxy)pyrimidine (0.66 g, 2.44 mmol), 4-methoxybenzylamine (0.34 g, 3.45 mmol), K2CO3 (0.37 g, 2.66 mmol), and DMF (15 mL) was heated at 100° C. for 1 h. The mixture was cooled, diluted with H2O (100 mL) and extracted with EtOAc (100 mL). The organic phase was washed twice each with saturated NaHCO3 solution and brine. The organics were dried (MgSO4) and concentrated to give the crude product. Flash chromatography on SiO2 using 1-3% MeOH in CH2Cl2 as the eluent gave the title compound (275 mg, 29%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.40-8.21 (m, 2H), 8.16 (dd, 1H, J=8.8, 1.7 Hz), 7.98 (br s, 0.5H), 7.73-7.55 (m, 1.5 H), 7.16 (br s, 1H), 6.85-6.71 (m, 3H), 6.37 (s, 1H), 4.43 (br s, 1H), 3.95 (br s, 1H), 3.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C>[NH2:30][C:26]1[O:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH2:1])[N:3]=3)[CH:8]=[CH:7][C:6]=2[CH:17]([C:16]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([Br:13])[CH:15]=2)[C:27]=1[C:28]#[N:29]
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Nc1ccc2cccc(O)c2n1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(N)nc32)cc(Br)c1OC
Temperature: 90 °C
Reaction time: 144 h

Procedure:
2-Amino-8-hydroxyquinoline (192 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were suspended in 25 ml ethanol at room temperature, charged with DABCO (33 μl, 0.3 mmol) and then stirred at 90° C. under LC-MS control for 6 days. The desired product was formed as a main component with some side products and a small amount of starting material was left. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and stirred for over night at room temperature. Thus resulting precipitates were collected by filtration, washed well with 1:1 mixture of ethanol/water and finally with small portion of 10% ethyl acetate in cyclohexane and then dried under high vacuum to get pure solids (202 mg, 0.45 mmol, 45%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]O)=[CH:3][CH:2]=1.[Cl-:10].S(Cl)([Cl:13])=O>C(Cl)Cl>[ClH:13].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][Cl:10])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: [Cl-]
Reactant: OCCc1ccncc1
Solvent: ClCCl
Product: Cl
Product: ClCCc1ccncc1

Procedure:
Furthermore 4-picolyl chloride hydrochloride or 4-picolyl bromide hydrobromide is converted to the free base by rendering the salt basic in ethanol, and then reacting with sodium or potassium cyanide (1.05 equivalents) to form the corresponding nitrile. The nitrile is solvolized in ethanol with aqueous hydrochloride acid to form ethyl 4-picolylacetate [cf. Rising et al., J. Am. Chem. Soc. 50, 1211 (1928)]. The latter is reduced with Red-al in benzene-tetrahydrofuran and isolated by the method of Examples 9 and 10, yielding 2-(4-pyridyl)ethanol. The alcohol is converted to corresponding chloride by reaction with thionyl chloride in refluxing methylene chloride [cf. Gilman et al., Rec. trav. chim. 51, 93 (1932)]. The 2-(4-pyridyl)ethyl chloride hydrochloride which forms is isolated by evaporation.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[C:11]12[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=1[S:18][C:17]1[C:16](=[O:24])[NH:15][N:14]=[CH:13][C:12]2=1.C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>O1CCOCC1>[Br:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([N:15]2[C:16](=[O:24])[C:17]3[S:18][C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:11]=4[C:12]=3[CH:13]=[N:14]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=c1[nH]ncc2c3c(sc12)CCCC3
Reactant: O=Cc1c(Br)cncc1Br
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1c(Br)cncc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 100 °C
Yield: 27 %

Procedure:
To a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 3,5-dibromoisonicotinaldehyde (200 mg, 0.76 mmol), 8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one 191d (160 mg, 0.76 mmol), and cesium carbonate (176 mg, 1.5 mmol). Cuprous iodide CuI (100 mg, 0.76 mmol) and 4,7-dimethoxy-1,10-phenanthroline (127 mg, 0.52 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on flash column eluting with EtOAC/PE (1:2) to afford 116a (80 mg, 30%). MS: [M+H]+ 390.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[H][H].C1(C)C=CC(S(O[CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])(=O)=O)=CC=1>CCCCCC.CN(C)C(=O)C.C1C=CC=CC=1.CCCCCC>[F:29][C:25]([F:30])([CH:26]([F:28])[F:27])[CH2:24][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
After 1.90 g (43.5 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 25 ml of N,N-dimethylacetamide and 5.3 g (43 mmol) of 4-hydroxybenzaldehyde were gradually added to the suspension at 0° C. under nitrogen atmosphere. When generation of hydrogen gas stopped, 11.4 g (39 mmol) of 2,2,3,3-tetrafluoropropyl p-toluenesulfonate were added to the reaction mixture, followed by heating of the resulting mixture at 120° C. with stirring for 2 hours and 15 minutes. After the reaction mixture was cooled, a mixed solvent of benzene-hexane (1:1) was added thereto and the resulting mixture was washed with water. After drying, the solvent was distilled off to obtain 8.85 g (yield: 96%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([S:8][C:9]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:10]=2[C:11](O)=[O:12])[CH:7]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[Cl:1][C:2]1[C:7]2[C:11](=[O:12])[C:10]3[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][C:14]=3[O:20][CH3:21])[S:8][C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c(C(=O)O)c1Sc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(OC)c2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of 19.7 g (0.053 mol) of the above benzoic acid, 600 ml of trifluoroacetic acid, and 300 ml of trifluoroacetic anhydride was stirred at 50° C. for four hours, treated with an additional 70 ml of trifluoroacetic anhydride, and stirred at 50° C. for 20 hours. The reaction mixture was poured into 9 l of H2O and the precipitate that accumulated was collected and dried to give 16.4 g of 1-chloro-5,8-dimethoxy-4-nitro-9H-thioxanthen-9-one, mp 222°-228° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([NH2:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:21]1[CH:36]=[CH:35][C:24]([CH2:25][N:26]2[C:30]([CH2:31][C:32](O)=[O:33])=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([NH:14][C:32](=[O:33])[CH2:31][C:30]2[N:26]([CH2:25][C:24]3[CH:35]=[CH:36][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)[CH:27]=[N:28][CH:29]=2)[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1
Reactant: COC(=O)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5-amino piperidine (134 mg, 0.520 mmol), [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid (147 mg, 0.520 mmol), HOBT (73,8 mg, 0.546 mmol), EDC (104 mg, 0.546 mmol), and Et3N (65.2 uL, 0.468 mmol) were dissolved in DMF (4 mL) and stirred at ambient temperature overnight. The solution was concentrated under reduced pressure and the residue was chromatographed (silica gel, 0.5-2% MeOH/CH2Cl2 with NH4OH) to give the title compound. 1H NMR (CDCl3) d 7.64 (d, 2H, J=8 Hz), 7.52 (s, 1H), 7.19 (d, 2H, J=8 Hz), 6.90-7.05 (m, 1H), 6.98 (s, 1H), 5.22-5.35 (m, 2H), 3.78-3.91 (m, 2H), 3.69 (s, 3H), 3,57-3.64 (m, 1H), 3.45-3.56 (m, 1H), 3.34 (s, 2H), 3.05-3.30 (m, 1H), 2.55-2.68 (m, 1H), 2.05-2.13 (m, 1H), 1.55-1.70 (m, 1H), 1.42 (s, 9H). FAB MS 482 (M+1)
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([NH2:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[IH:17].CS[C:20]1[NH:21][CH2:22][CH2:23][N:24]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)C.CCOCC>[IH:17].[NH:21]1[CH2:22][CH2:23][NH:24][C:20]1=[N:16][CH:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: CSC1=NCCN1
Reactant: NC1c2ccccc2C=Cc2ccccc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: C1=Cc2ccccc2C(N=C2NCCN2)c2ccccc21
Reaction time: 8 h

Procedure:
1.04 grams (0.005 mole) of 5H-dibenzo[a,d]cyclohepten-5-ylamine, 1.22 grams (0.005 mole) of 2-methylmercapto-4,5-dihydroimidazole hydroiodide, and 1.5 milliliters of triethylamine were mixed together in 20 milliliters of ethanol and heated at reflux temperature for 16 hours. Thereafter most of the ethanol was evaporated, some n-butanol added and the resulting mixture heated under reflux for 15 hours. At the end of this period, the solvent was removed under reduced pressure, and residue obtained to which was added first, aqueous sodium bicarbonate, then ether and the resulting mixture stirred and decanted to recover the non-dissolving solid as residue. The solid was stirred overnight with ether, filtered and crystallized from ethanol. It was purified by chromatographing on a silica gel column employing 6 percent methanol in chloroform as eluant to obtain the desired N-(2-imidazolidinylidene)-5H-dibenzo[a,d]cyclohepten-5-amine hydroiodide product. Elemental analyses were as follows:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31]([N:12]1[C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:11]1)(=[O:33])=[O:32]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C

Procedure:
By an operation similar to that in Reference Example 32 and using tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (305 mg), and 2,5-difluorobenzenesulfonyl chloride (319 mg), the title compound was obtained as a colorless oil (yield 160 mg, 33%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)=[NH:9].[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C1COCC1>[C:27]([N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([NH:7][CH2:6][C:5]2[C:4]([O:3][CH3:2])=[CH:24][CH:23]=[CH:22][C:21]=2[O:25][CH3:26])=[NH:9])[S:12][CH:13]=1)(=[O:29])[CH3:28]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2)cs1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2C(C)=O)cs1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 100 mg (0.25 mmol) N-(2,6-dimethoxybenzyl)-N′-(4-pyrrolidine-2-yl-1,3-thiazole-2-yl)guanidine hydrochloride, Example 147, 0.021 ml acetyl chloride and 0.04 ml pyridine in 10 ml THF were stirred for 1 hour at 5° C. and then 4 hours at room temperature. Chromatography of the crude product on RP-silica gel (Chromabond column, acetonitrile/water+0.1% glacial acetic acid; 0-100%) yielded 33 mg of the desired product; ESI-MS [M+H+]=404.15.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:38])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:38][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:36])([F:35])[F:37])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
Lithium hydroxide monohydrate (0.015 g, 0.36 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.047 g, 0.091 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-fluoro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.031 g, 68%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.57 (d, J=7.83 Hz, 1 H) 7.98-8.13 (m, 6 H) 7.90 (s, 1 H) 7.53 (d, J=8.31 Hz, 2 H) 7.38 (td, J=8.80, 2.40 Hz, 1 H) 6.61 (dd, J=11.00, 2.50 Hz, 1 H) 3.84 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C26H17F4O4S [(M−H)−] 501, obsd. 501.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].Cl[CH2:15][O:16][CH3:17].Cl.[CH3:19]N(C)C=O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[O:11][CH2:15][O:16][CH3:17]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COCOc1cc(F)ccc1C(=O)OC
Reaction time: 48 h

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0 g) in N,N-dimethylformamide (5 mL) were added sodium hydride (60% 1.0 g) and (chloromethyl)methyl ether (2.1 g) at room temperature, and this mixture was stirred for 48 hours at the same temperature. This reaction mixture was poured into 2 mol/L hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.22 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[C:9](=[O:10])[NH:8][CH2:7][CH2:6][NH:5]1.[Cl:11][CH:12]([Cl:16])[C:13](Cl)=[O:14]>O.C(Cl)Cl>[Cl:11][CH:12]([Cl:16])[C:13]([N:5]1[CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH:4]1[CH3:3])=[O:14]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1NCCNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1C(=O)NCCN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
A solution of 8 g (0.2 mole) of sodium hydroxide in 15 ml of water was added to a solution of 20 g (0.18 mole) of 2-methyl-piperazin-3-one in 150 ml of methylene chloride. 26.6 g (0.18 mole) of dichloroacetyl chloride were then added dropwise at from 10° to 15° C. The mixture was stirred at 25° C. for 10 hours and the precipitated crude product was filtered off with suction, washed with water and recrystallized from a 2:1 mixture of isopropanol and H2O to give 14.4 g (36% of theory) of 1-dichloroacetyl-2-methyl-3-oxo-piperazine of melting point 167°-168° C.