Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.NC(=O)C[C@@H](NC(OCC1C=CC=CC=1)=O)C(O)=O.N1C=CC=CC=1.[NH2:47][CH2:48][C@@H:49]([NH:53][C:54]([O:56][C:57](=O)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C:50]([OH:52])=[O:51]>O.CN(C)C=O>[NH2:47][CH2:48][C@@H:49]([NH:53][C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C:50]([OH:52])=[O:51]
Reactant: NC[C@@H](NC(=O)OC(=O)c1ccccc1)C(=O)O
Agent: NC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: NC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (6.45 g., 15.0 mmole) is dissolved in water-dimethylformamide 1:1 (80 ml.) and (R)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutanoic acid (2.4 g., 9.0 mmole) is added over a 10 minute period. The reaction is allowed to stir at room temperature for 30 minutes, until dissolution occurs. Pyridine (1.62 ml., 20 mmole) is added dropwise over a 5 minute period. The reaction is allowed to stir for 3 hours then stripped of solvent to yield a yellow precipitate. This semi-solid is triturated with a combination of isopropanol:ethyl ether. The precipitate is filtered and dried over phosphorus pentoxide to yield 1.35 g. of (R)-3-amino-2-[[(benzoyloxy)carbonyl]amino]propanoic acid as a white solid.
Reaction SMILES: N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)N.N[C@H](C(N)=O)CC(=O)N.N1C(=O)CC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC(NCC(NCC(N[C@H:79]([C:82]([NH:84][C@H:85]([C:90]([OH:92])=[O:91])[CH2:86][C:87](=[O:89])[NH2:88])=[O:83])[CH2:80][OH:81])=O)=O)=O)=O)CCC(=O)N)=O)CO)=O)CCCCN)=O)C)=O.[NH:93]1[C:97](=[O:98])[CH2:96][CH2:95][C@H:94]1[C:99]([NH:101][C@H:102]([C:104]([NH:106][C@H:107]([C:113]([NH:115][C@H:116]([C:119]([NH:121][C@H:122]([C:128]([NH:130][CH2:131][C:132]([NH:134][C@H:135]([C:138]([NH:140][C@H](C(O)=O)CC(=O)N)=[O:139])CO)=[O:133])=[O:129])[CH2:123][CH2:124][C:125](=[O:127])[NH2:126])=[O:120])[CH2:117][OH:118])=[O:114])[CH2:108][CH2:109][CH2:110][CH2:111][NH2:112])=[O:105])[CH3:103])=[O:100]>>[NH:93]1[C:97](=[O:98])[CH2:96][CH2:95][C@H:94]1[C:99]([NH:101][C@@H:102]([C:104]([NH:106][C@H:107]([C:113]([NH:115][C@H:116]([C:119]([NH:121][C@H:122]([C:128]([NH:130][CH2:131][C:132]([NH:134][CH2:135][C:138]([NH:140][C@H:79]([C:82]([NH:84][C@H:85]([C:90]([OH:92])=[O:91])[CH2:86][C:87](=[O:89])[NH2:88])=[O:83])[CH2:80][OH:81])=[O:139])=[O:133])=[O:129])[CH2:123][CH2:124][C:125](=[O:127])[NH2:126])=[O:120])[CH2:117][OH:118])=[O:114])[CH2:108][CH2:109][CH2:110][CH2:111][NH2:112])=[O:105])[CH3:103])=[O:100]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)C[C@H](N)C(N)=O
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: C[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
Asn9 is replaced by: Asp, Gln, -Ala-NH, and Asn-NH2, and the polypeptides, PyroGlu-Ala-Lys-Ser-Gln-Gly-Gly-Gly-Ser-Asn, and PyroGlu-Ala-Lys-Ser-Gln-Gly-Ser-Asn.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([Br:5])([Br:4])[Br:3].C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].O>C(OCC)C>[Br:3][C:2]([Br:5])([Br:4])[CH2:1][O:6][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: OCC(Br)(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(Br)(Br)Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
A first solution comprising tribromoethanol (50 g, 177 mmol) and triethylamine (19.73 g, 195 mmol) dissolved in 70 g of diethylether was prepared. A second solution comprising methacryloyl chloride (20.39 g, 195 mmol) dissolved in 70 g of diethylether was added dropwise to the first solution followed by stirring for four hours at room temperature. The resulting solution was then added to water, and the organic phase was extracted. The organic phase was distilled to yield 32.85 g of TBEMA (52.9% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:2]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:32])[NH:25][CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1)=[O:16]>ClCCl>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][NH:25][C:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:9][CH2:10]2)=[O:16])=[CH:23][CH:22]=1)=[O:32]
Reactant: CC(C)(C)CCNC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: c1cncc(CN2CCNCC2)c1
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)c1ccc(OC(=O)N2CCN(Cc3cccnc3)CC2)cc1
Reaction time: 16 h

Procedure:
The title product was prepared from 1-pyridin-3-ylmethyl-piperazine was dissolved in dichloromethane (5 ml). 4-(3,3-Dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (metod C) (88%, light yellow oil). HPLC-MS m/z=425.4 (M+1), Rt: 2.33 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[C:9]1[S:13][CH:12]=[CH:11][S:10]1)[C:5]([O:7]C)=[O:6]>CO.[OH-].[K+].CO>[CH3:1][O:2][C:3](=[O:14])[C:4](=[C:9]1[S:13][CH:12]=[CH:11][S:10]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C(=O)OC)=C1SC=CS1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C(=O)O)=C1SC=CS1
Yield: 89.9 %

Procedure:
(1,3-Dithiol-2-ylidene)malonic acid dimethyl ester (232 mg) prepared according to the procedure described in JP-76-48666, was suspended in methanol (0.1 ml) and iN KOH/methanol (3.0 ml) was added. The reaction mixture was refluxed for 1 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted to 2 with 1N HCl. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound (196 mg) as a pale yellow powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:25]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:49])[NH:39][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)([CH3:42])[CH3:41])[CH:33]=4)=[CH:22][C:17]=3[C:18]=2[C:19]([OH:21])=O)=[CH:10][CH:9]=1.[CH3:50][N:51](C=O)C.CCN(C(C)C)C(C)C.CN>ClCCCl.CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:25]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:28])=[O:29])[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:49])[NH:39][C:40]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([CH3:41])[CH3:42])[CH:33]=4)=[CH:22][C:17]=3[C:18]=2[C:19]([NH:51][CH3:50])=[O:21])=[CH:10][CH:9]=1
Reactant: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1cccc(C(=O)NC(C)(C)c2ccccc2)c1)S(C)(=O)=O
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
Oxalyl chloride (22 μL, 0.250 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylic acid (50 mg, 0.083 mmol) in DCE (832 μL) at rt. DMF (3 μL, 0.042 mmol) was added. The mixture was allowed to stir for 30 min, concentrated and diluted with THF. DIEA (59 μL, 0.333 mmol) and methanamine (208 μL, 0.416 mmol, 2M in THF) was added. It was allowed to stir overnight. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46-8.56 (1H, m), 8.36 (1H, s), 7.97-8.05 (3H, m), 7.94 (1H, s), 7.86 (1H, d, J=7.78 Hz), 7.59-7.67 (2H, m), 7.53 (1H, t, J=7.65 Hz), 7.35-7.42 (4H, m), 7.29 (2H, t, J=7.78 Hz), 7.17 (1H, t, J=7.28 Hz), 3.06 (3H, s), 3.01 (3H, s), 2.82 (3H, d, J=4.52 Hz), 1.69 (6H, s). LC-MS retention time: 1.51 min; m/z (MH+): 614. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.89 min, purity=92%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 mm, Rt=12.11 min, purity=91%.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8]3[CH:19](CC(O)=O)[CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=[C:4]([F:26])[CH:3]=1.[N+](=C)=[N-].C(C1C(=O)C(Cl)=C(Cl)C(=[O:35])C=1C#N)#N.C[CH2:45][O:46][C:47]([CH3:49])=[O:48]>C1COCC1.O.[Cl-].[Na+].O>[CH3:45][O:46][C:47](=[O:48])[CH2:49][CH:19]1[C:8]2[N:9]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:10]3[C:2]([Br:1])=[CH:3][C:4]([F:26])=[CH:5][C:6]=3[C:7]=2[C:21](=[O:35])[CH2:20]1
Reactant: CCOC(C)=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C(O)CC1CCc2c1n(Cc1ccc(Cl)cc1)c1c(Br)cc(F)cc21
Agent: C=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC1CC(=O)c2c1n(Cc1ccc(Cl)cc1)c1c(Br)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The methyl ester of the compound of Example 1 step 5 (1.00 g, preapared by treating the corresponding acid with excess diazomethane) in 10 mL of a 9:1 THF/H2O solution was treated with 2.52 g of DDQ. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture at this time was poured into a separatory funnel containing EtOAc and brine. The combined organic layers were washed with water, brine, dried over anhydrous MgSO4 and concentrated. The resulting material was further purified by flash chromatography eluting with 30% EtOAc/hexane. The chromatography procedure was repeated an additional two times. 350 mg of the above ketone was obtained as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:12])=[C:7]([CH2:9][C:10]#N)[CH:8]=1.[OH-:13].[Na+].[OH2:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:12])=[C:7]([CH2:9][C:10]([OH:15])=[O:13])[CH:8]=1
Reactant: COc1ccc(Br)c(CC#N)c1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Br)c(CC(=O)O)c1
Temperature: 25 °C

Procedure:
5-Methoxy-2-bromophenylacetonitrile (52.8 g, 0.23 mol) is dissolved in ethanol (250 mL) and stirred at room temperature. Sodium hydroxide (9.3 g, 0.47 mol) is dissolved in water (150 mL) and added to the solution of the nitrile. The mixture is heated to reflux temperature for 12 hours and then cooled to room temperature. Most of the ethanol is removed using a rotary evaporator and the residual aqueous solution adjusted to pH 4 with 3 N HCl. The solid which forms is isolated by filtration and washed with water. Air drying gives 5-methoxy-2-bromophenylacetic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:20]=O)[S:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:22][NH2:23].CO.CO>O1CCCC1>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH2:20][NH:23][CH3:22])[S:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(2-fluoropyridin-3-yl)-5-[(pyridin-2-yl)thio]thiophene-2-carbaldehyde (270 mg) in tetrahydrofuran (2 mL) were added 40% methylamine-methanol solution (0.9 mL) and methanol (2 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (3 mL), and sodium tetrahydroborate (222 mg) was added at 0° C. The mixture was stirred at room temperature for 1 day and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 286 mg, yield quantitative).
Reaction SMILES: CO[C:3](=[O:30])[CH2:4][C:5](=[O:29])[CH2:6][C:7]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20].COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:24]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]([F:20])([F:22])[F:21])[O:23][C:3](=[O:30])[CH2:4][C:5](=[O:29])[CH2:6]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1ccccc1OC(F)(F)F)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: O=C1CC(=O)OC(CCC#Cc2ccccc2OC(F)(F)F)(C2CCCC2)C1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-5-hydroxy-3-oxo-9-(2-trifluoromethoxy-phenyl)-non-8-ynoic acid methyl ester (72 mg, 0.17 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 25 mg, 37%. 1H NMR (CDCl3) δ: 1.33-1.73 (m, 8H), 1.89-2.06 (m, 2H), 2.14-2.23 (m, 1H), 2.55 (t, J=7.58 Hz, 2H), 2.69 (d, J=16.17 Hz, 1H), 2.84 (d, J=16.17 Hz, 1H), 3.37 (s, 2H), 7.15-7.21 (m, 2H), 7.23-7.27 (m, 1H), 7.38-7.44 (m, 1H). MS (ESI): 393 (M−H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)=[O:7].Br.C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(C)c(OC)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C(=O)c2ccc(O)cc2)cc1O
Yield: 77.8 %

Procedure:
Demethylation of 114 g 3,4'-dimethoxy-4-methyl-benzophenone (0.445 mole) was effected by refluxing 15 hr. with a previously prepared mixture of 313.5 ml of 48% aqueous hydrobromic acid, 148 ml of acetic anhydride, and 148 ml of acetic acid. The isolated product melted at 173°-174° C. Recrystallization from ethanol/water yielded 79 g (0.346 mole) of 3,4'-dihydroxy-4-methylbenzophenone melting at 174°-175° C.
Reaction SMILES: C(OC(=O)[N:5]([C:7]1[C:16]2[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([OH:18])[N:8]=1)[NH2:6])C.CN(C)[CH:22]=[O:23]>>[Cl:17][C:12]1[C:11]2[NH:10][C:9](=[O:18])[N:8]3[C:22](=[O:23])[NH:6][N:5]=[C:7]3[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)N(N)c1nc(O)nc2c(Cl)cccc12
Reactant: CN(C)C=O
Product: O=c1[nH]nc2c3cccc(Cl)c3[nH]c(=O)n12
Temperature: 25 °C

Procedure:
1.27 g (0.0045 mol) of ethyl-8-chloro-2-hydroxy-quinazoline-4-yl-carbazate in 75 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, dried in a vacuum and recrystallized from methanol/tetrahydrofuran. Yield: 0.66 g (62%) of 7-chloro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. 348°-350° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: O=C1CCCC(=O)C1
Product: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Br
Temperature: 125 °C
Yield: 92.5 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125° C. under a stream of nitrogen for 4 hours. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) δ 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm−1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH2:6][CH2:7]2)=[CH:18][CH:17]=1
Reactant: NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1)NC1CCCCC1

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)homopiperazine (2.16 g; 7.7 mmole) in methylene chloride (30 ml) was stirred at room temperature with cyclohexyl isocyanate (1.05 g; 8.5 mmole) for one hour. The reaction mixture was concentrated under reduced pressure to an oil which was chromatographed on silica gel (methylene chloride/methanol/ammonium hydroxide: 97/2.5/0.5) to yield 1-{3-[4-(4-chlorobenzyl)homopiperazin-1-yl]propyl}-3-cyclohexylurea as a colorless oil. This oil was dissolved in ether and precipitated with ethereal hydrogen chloride to provide the title compound (2.25 g; 61% yield) as a white crystalline solid, m.p. 167°-175° C. (dec.).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=O)[CH3:4].[CH:9]([SH:12])(S)[CH3:10].CC1C=CC([S:20](O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:8][CH2:7][CH2:6][C:2]1[S:20][CH2:10][CH2:9][S:12][C:3]=1[CH3:4]
Reactant: CC(S)S
Reactant: CC(=O)C(Cl)CCCl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=C(CCCl)SCCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of 0.1 mole (15.4 g.) 3,5-dichloro-2-pentanone, 0.1 mole (9.4 g.) ethanedithiol and 0.3 mole PTSA was stirred at room temperature overnight. The product was taken up in toluene, washed with 5% sodium bicarbonate and water, dried over magnesium sulfate, filtered and the solvent removed. The product was distilled; bp. 114°-116°/0.7 mm. Yield 32%.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([CH:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=2)[C:13]#[N:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: Clc1ccnc2ccccc12
Agent: N
Product: COc1ccc(C(C#N)c2ccnc3ccccc23)cc1OC
Reaction time: 2 h

Procedure:
To 500 ml of liquid NH3 was added 35.4 g (0.2 mol) of 3,4-dimethoxyphenylacetonitrile and 11.7 g (0.3 mol) of NaNH2. The mixture was stirred for two hours, maintaining a temperature at -25° to -30°C by cooling in a dry ice/acetone bath. 4-Chloroquinoline (16.4 g, 0.1 mol) was added and the resulting mixture was allowed to stir at room temperature until all excess NH3 had evaporated. Benzene was added to the residue and water was added slowly to destroy excess NaNH2. The phases were separated and the aqueous phase was extracted with benzene. The combined benzene extracts were extracted with 9M HCl (2×150 ml). The acidic phase was washed with Et2O (500 ml), cooled and basified with concentrated NH4OH. The aqueous mixture was extracted with CHCl3 (500 ml). The CHCl3 extract was dried with MgSO4 and evaporated to give a quantitative yield of crude α-(4 -quinolinyl)-α-(3,4-dimethoxyphenyl)acetonitrile intermediate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:17])([F:16])[F:15])=[N:10][C:7]2=[N:8][CH:9]=1)([O-])=O.C(O)C.Cl.[H][H]>O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:15])([F:17])[F:16])=[N:10][C:7]2=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2nc(C(F)(F)F)n(O)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cnc2nc(C(F)(F)F)n(O)c2c1

Procedure:
6-Nitro-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)-pyridine (4.9 grams) was mixed with 100 milliliters of ethanol and 3 milliliters of concentrated hydrochloric acid, and 1 gram of 5 percent palladium or carbon was added to the mixture. The mixture was hydrogenated to a 3 mole-equivalent uptake of hydrogen. The reaction mixture was then filtered and evaporated, yielding a gummy solid residue which was taken up in 150 milliliters of water and used directly in the reaction reported in the following example.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18](=O)[CH3:19])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH2:27])[CH3:19])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 84.7 %

Procedure:
A mixture of 1-[4-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]ethanone (0.13 g, 0.45 mmol) and ammonium acetate (0.348 g, 4.52 mmol) in methanol (2.0 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, to the resultant mixture was added sodium cyanoborohydride (57 mg, 0.91 mmol). The reaction was heated at 65° C. for another 4 hours. After cooling to room temperature, the reaction was quenched with aqueous saturated NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.11 g), which was used directly in the next step. LCMS calculated for C16H12ClFN(M-NH2)+: m/z=272.1. Found: 272.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1>>[CH3:20][NH:19][C:17]([C:13]1[CH:12]=[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[Cl:9])[CH:16]=[CH:15][N:14]=1)=[O:18]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(Cl)c1
Product: CNC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1

Procedure:
Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.