Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:19]([F:22])([F:21])[F:20])[O:8][C:9]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=2[C:11]=1[CH2:12][CH3:13])=[O:5])C.[OH-].[Na+].CCCCCC>C1COCC1.C(O)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:9]2[O:8][CH:7]([C:19]([F:21])([F:20])[F:22])[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH2:12][CH3:13])[C:10]=2[CH:14]=1
Reactant: CCOC(=O)C1=C(CC)c2cc(Cl)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1=C(C(=O)O)C(C(F)(F)F)Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.8 %

Procedure:
The ester from Step 1 (0.282 g, 0.842 mmol) was dissolved in a THF-EtOH—H2O mixture (10 mL, 7:2:1). The resulting solution was treated with aqueous sodium hydroxide (0.340 mL, 0.842 mmol of a 2.5 N solution) and was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water 10 mL). Diethyl ether (10 ml ) was added and the resulting mixture acidified by the addition of a few drops of concentrated HCl. The diethyl ether layer was separated, and the aqueous phase was extracted with additional ether(2×10 mL). The ether extracts were combined, dried over MgSO4, filtered, and evaporated to yield a clear oil. Addition of hexane (10 mL) resulted in the formation of a white precipitate which was collected by vacuum filtration to afford the title compound (0.064 g, 25%) as a white powder: mp 170.9–172.1° C. 1H NMR (CDCl3/300 MHz) 7.47 (d, 1H, J=2.4 Hz), 7.30 (dd, 1H, J=2.4, 8.7 Hz), 6.96 (d, 1H, J=8.7 Hz), 5.76 (q, 1H, J=7.0 Hz), 3.08 (q, 2H, J=7.6 Hz), 1.27 (t, 3H, J=7.5 Hz). FABLRMS m/z 305.2 (M−H).ESHRMS m/z 305.0185 (M−H, Calc'd. 305.0192). Anal. Calc'd for C13H8ClF3O3: C, 50.92; H, 3.29; Cl, 11.56. Found: C, 50.68; H, 3.18; Cl, 11.64.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Yield: 96.7 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (5 g, 30 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (21 mL, 92 mmol) in methanol (200 mL) at 45° C. for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (9 g, 97%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:9])=[CH:3][CH:2]=1.CI.[CH2:19](O)C>O>[CH3:19][S:9][C:8](=[N:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Reactant: CCO
Solvent: CI
Solvent: O
Product: CSC(=Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a 2 l flask were added 342 g of thiocarbanilide, 240 g of methyl iodide and 350 cc of ethanol and the mixture was refluxed for 2 hours. After cooling the mixture to a room temperature, a small amount of water was added and the mixture was allowed to stand to precipitate the raw product, which was then filtered off and dissolved in 12 l of hot water. After filtration, the filtrate was converted to an alkaline solution by addition of NaOH to precipitate the product. The product was filtered and washed well until the filtrate became neutral. After drying, the product was recrystalized in 1 l of ethanol to give S-methyl-N,N'-diphenylisothiourea.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CCO.Cl.[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([N:42]([CH3:44])[CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1>O>[ClH:31].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[C:39]([N:42]([CH3:44])[CH3:43])[CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccc(N(C)C)cc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amide E5 (228 mg, 0.62 mmol) in 1:2 EtOH:H2O (20 mL) were sequentially added c.HCl (0.17 mL, 5.61 mmol) and 4-chloro-6-dimethylaminoquinoline (03) (140 mg, 0.68 mmol), and the resulting mixture was refluxed for ˜12 h. MS and TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) after this time showed some starting material still present in the reaction mixture, thus more 03 (140 mg, 0.68 mmol) was added. After a further few hours refluxing, TLC showed the reaction was complete, and thus solvent was removed under reduced pressure. The residue was crystallized from MeOH:EtOAc to afford Cpd. P as an (extremely fine) amorphous yellow solid (170 mg, 51%). 1H NMR [(CD3)2SO] δ2.28 [s, 3H], 3.15 [s, 6H, ArN(CH3)2], 6.21 [br s, 1 H, ArH], 6.89 [d, J=6.71 Hz, 1 H, ArH], 7.65 [m, 5 H, ArH], 7.82 [m, 4 H, ArH & ArNH2], 7.96 [d, J=9.39 Hz, 1 H, ArH], 8.18 [d, J=8.57 Hz, 2 H, ArH], 8.35 [t, J=12.38, 6.19 Hz, 1 H, ArH], 10.44 [br s, 1 H, ArH], 10.65 [br s, 1 H, ArNHAr], 10.71 [s, 1 H, ArNHAr], 12.75 [br s, 1 H, ArC(O)NH], 14.56 [d, J=4.10 Hz, 1 H, quinolinyl N+H]. LCMS (APCI+): 506 (100%). HPLC: 97.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:41])[C:32]3[N:36]=[C:35]([CH2:37][O:38][CH3:39])[NH:34][C:33]=3[CH:40]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:41])[C:32]6[N:36]=[C:35]([CH2:37][O:38][CH3:39])[NH:34][C:33]=6[CH:40]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1nc2c(C)cc(Oc3cc(N4CCC(N5CCc6cc(OC)ccc6NC5=O)CC4)ncn3)cc2[nH]1

Procedure:
52 mg (0.19 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo[d]imidazole and 0.07 mL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH2:23].C(O)C>C(O)(=O)C.O>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:22][N:23]=[CH:14][C:13]1[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1
Reactant: NNc1ccccn1
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccc3)cc2C=NNc2ccccn2)o1
Yield: 95 %

Procedure:
Stir an admixture of 2 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde, 0.92 g of 2-hydrazinopyridine, 50 ml of ethanol and 2 drops of glacial acetic acid for 36 hours at room temperature. Cool the admixture and then form a precipitate with 50 ml of water to obtain a 95% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde-(2-pyridyl)hydrazone [m.p. 228° to 231° C (with decomposition) from dimethylformamide/water].
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:7][C:6]1=[O:20])C.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C(=O)([O-])[O-].[Na+].[Na+].NC1N=CC2C(=O)CC(C3C=CC(Cl)=CC=3)CC=2N=1>O>[NH2:24][C:23]1[N:25]=[CH:4][C:5]2[C:6](=[O:20])[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[CH2:9][C:10]=2[N:22]=1
Reactant: COc1ccccc1C1CC(=O)C(=CN(C)C)C(=O)C1
Reactant: N=C(N)N
Agent: Cl
Agent: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Agent: O=C([O-])[O-]
Solvent: O
Product: COc1ccccc1C1CC(=O)c2cnc(N)nc2C1
Temperature: 25 °C

Procedure:
The title compound was prepared from 2-dimethylaminomethylene-5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (484 mg, 1.77 mmol) from stage 1, guanidine hydrochloride (253 mg, 2.55 mmol) and sodium carbonate (469 mg, 4.42 mmol), following the procedure described for the synthesis of 2-amino-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/a stage 2) except that the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature; water (5 ml) was then added. The precipitate formed was filtered and washed with water (5 ml) to afford the title molecule as a brown powder.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]([CH3:36])=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].CO.[OH-].[Na+]>C1COCC1>[CH3:6][CH:5]([CH3:7])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]([CH3:36])=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4cc3C)cc2)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2ccccc2nc1OCc1ccc(-c2ccc(S(=O)(=O)NC(C(=O)O)C(C)C)cc2)cc1
Reaction time: 72 h
Yield: 51.3 %

Procedure:
3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester (203 mg, 0.39 mmol, 1 equiv.) was dissolved in THF (8 mL) and MeOH (4 mL) and hydrolyzed with 1N NaOH (5.83 mL, 5.83 mmol, 13 equiv.). After stirring for 3 days, solvent was removed and the residue was dissolved in H2O. The mixture was then acidified to pH 3 using 1N HCl. Solid precipitated from the mixture was collected by filtration and washed with water. After drying in vacuum oven, 101 mg of 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid was obtained in 76.3% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][CH:16]([CH3:19])[CH2:17][CH3:18])[C:9](O)=[O:10]>>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][CH:16]([CH3:19])[CH2:17][CH3:18])[C:9]([Cl:3])=[O:10]
Reactant: CCC(C)Cc1ccc(C(=O)O)cc1Br
Reactant: O=S(Cl)Cl
Product: CCC(C)Cc1ccc(C(=O)Cl)cc1Br
Yield: 98.1 %

Procedure:
Thionyl chloride (118 g) was added to the 3-bromo-4-(2'-methylbutyl)benzoic acid (100 g, 0.37 mol) followed by refluxing the mixture for 2 hours and distilling off excess thionyl chloride under reduced pressure to obtain 3-bromo-4-(2'-methylbutyl)benzoic acid chloride (105.1 g).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:26][CH2:27][C:28](Cl)=[O:29].O>C(OCC)(=O)C>[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:28](=[O:29])[CH2:27][Cl:26])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1.68 ml of triethylamine were added to a solution of 3.00 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine in 60 ml of ethyl acetate, and the resulting mixture was cooled with ice, after which 0.96 ml of 2-chloroacetyl chloride was added. The reaction mixture was then stirred at room temperature for 1 hour, after which it was mixed with water and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 3.40 g (yield 87%) of the title compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCC1CCCCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][C:23]1[CH:24]=[CH:25][C:26](C(OC)=O)=[N:27][CH:28]=1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(Cl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-chlorophenylacetic acid (326.5 g, 1.91 mol, 0.95 eq) in THF (1.82 L) at −78° C. was slowly added NaHMDS (1M solution in THF, 3.82 L, 3.82 mol, 2 eq) over 2 h 45 min while keeping the temperature below −65° C. After the addition was complete, the reaction mixture was stirred for 30 min at −78° C. A solution of methyl 5-chloropicolinate (326.5 g, 1.91 mol, Example 121, Step A) in THF (0.9 L) was added to the above solution at −78° C. over 30 min. The reaction was stirred for another 1 h and then allowed to warm to ambient temperature overnight. The reaction mixture was slowly transferred into a sat. aq. ammonium chloride solution (4 L), extracted with ethyl acetate (2×8 L), and then the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (eluent: DCM) provided the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=2)[N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=1.CNCCNC>[Cu]I.O1CCOCC1>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:13](=[O:19])[N:14]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=2)[N:3]=1
Reactant: Clc1cccc(I)c1
Reactant: Cc1cc[nH]c(=O)c1-c1ccc2nc(N)ncc2c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccn(-c2cccc(Cl)c2)c(=O)c1-c1ccc2nc(N)ncc2c1
Temperature: 85 °C

Procedure:
To a resealable tube was added a mixture of 3-(2-aminoquinazolin-6-yl)-4-methylpyridin-2(1H)-one (0.050 g, 0.20 mmol), potassium phosphate (0.084 g, 0.40 mmol), and copper(I) iodide (0.0075 g, 0.040 mmol) followed by Dioxane (2 mL), 1-chloro-3-iodobenzene (0.027 ml, 0.22 mmol) and N1,N2-dimethylethane-1,2-diamine (0.009 ml, 0.079 mmol). The resealable tube was purged with argon, sealed, and heated at 85° C. for 48 hrs. The crude mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 3-10% MeOH in CH2Cl2 with 1% NH4OH to afford 3-(2-amino-6-quinazolinyl)-1-(3-chlorophenyl)-4-methyl-2(1H)-pyridinone as an off-white solid. M+H+=363.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[CH2:5].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:4]([C:3]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:2]=1[O:1][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][O:12][CH3:11])=[CH:23][CH:22]=1)=[CH2:5]
Reactant: C=Cc1cc(I)ccc1O
Reactant: COCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(I)ccc1OC(=O)c1ccc(OCOC)cc1
Temperature: 23 °C
Reaction time: 21 h
Yield: 79 %

Procedure:
To a stirred solution of 2-hydroxy-5-iodostyrene, 4-(methoxymethoxy)benzoic acid, and DCC in methylene chloride at 23° C. was added DMAP, and the resulting mixture was stirred at 23° C. for 21 hours. The reaction mixture was then filtered over celite and concentrated in vacuo. Purification by flash chromatography (SiO2, hexanes:ethyl acetate 5:1) yielded (2-vinyl-4-iodophenyl)-4-methoxymethoxybenzoate as a colorless solid (4.6 g, 79%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]([C:15]([NH2:17])=[S:16])[NH:12][CH:13]=O>[OH-].[Na+]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15](=[S:16])[NH:17][CH:13]=[N:12]1
Reactant: NC(=S)N(NC=O)C1CCc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Product: S=c1[nH]cnn1C1CCc2ccccc2C1
Yield: 44.2 %

Procedure:
A solution of N-[(1,2,3,4-tetrahydronaphthalen-2-yl)(aminothiocarbonyl)amino]formamide (0.6 g, 2.4 mmol) in 10 mL of 10% sodium hydroxide was heated at 70° C. for 30 minutes. The solution was cooled, acidified with dilute. hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane and filtration gave 2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro[1,2,4]triazole-3-thione (0.25 g. 1.06 mmol), m.p. 200.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[CH:4][CH2:3][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CCOC(C)=O.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1(C(=O)OCC)CC=CCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCCCO1
Reaction time: 3 h

Procedure:
A stirred suspension of 10% Pd—C (0.511 g, 0.480 mmol) in a solution of diethyl 2H-pyran-2,2(3H,6H)-dicarboxylate (2.74 g, 12.00 mmol) in EtOAc (50 mL) was hydrogenated under balloon pressure for 3 h. The suspension was filtered and the filtrate was evaporated to dryness to afford diethyl tetrahydro-2H-pyran-2,2-dicarboxylate as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.33-4.24 (m, 4H), 3.88-3.81 (m, 2H), 2.15-2.08 (m, 2H), 1.79-1.69 (m, 2H), 1.67-1.57 (m, 2H), 1.33-1.28 (m, 6H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[C:21]=1[CH2:22]Br.O>CN(C=O)C>[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[C:21]=1[CH2:22][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
Cs2CO3 (10.8 g, 33.3 mmol) was added at room temperature to 8-hydroxy-2-methylquinoline (5 g, 33.3 mmol) in DMF (65 ml). After 30 min, 2,6-dichloro-3-nitrobenzyl bromide (13 g, 45.6 mmol) was added. After 18 h, H2O was added and the precipitate was filtered off with suction and washed with EA (50 ml), the title compound being obtained as an amorphous substance.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH2:29][O:30][CH3:31])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]=1[CH3:39])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH2:29][O:30][CH3:31])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:16]=1[CH3:39])#[N:14]
Reactant: COCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 2 h
Yield: 52.8 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (70 μl, 552 μmol) was added at 150° C. to a dimethyl sulfoxide (7 ml) solution of 4-cyano-7-fluoro-N-(2-methoxyethyl)-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-122) (169 mg, 460 μmol) and triethylamine (83 μl, 598 μmol), followed by stirring at the same temperature for 2 hours. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (20:1, v/v) gave the entitled compound (112 mg, 53%) as an amorphous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27]>C1COCC1.CCOC(C)=O>[CH3:13][C:12]([Si:9]([CH3:11])([CH3:10])[O:8][C:4]1[CH:3]=[C:2]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([OH:27])=[O:21])[CH:7]=[CH:6][CH:5]=1)([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCC(=O)O)c1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Under argon, to a solution of [(3-bromophenyl)oxy](1,1-dimethylethyl)-dimethylsilane (1.5 g, 5.22 mmol) in THF (60 mL) at −78° C., was added dropwise n-BuLi (3.6 mL, 1.6 M in hexanes), 20 min after the addition, this solution was added to a solution of dihydro-2,5-furandione (630 mg, 6.26 mmol) in THF (10 mL) under argon at −78° C. 15 min later, the reaction mixture was slowly warmed to rt overnight. The reaction mixture was diluted with EtOAc (50 mL), then extracted with NaOH (20 ml, 1.0 N). Aquaous layer was acidified with HCl (1.0N) until pH=2, then extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless crystal (546 mg, 54%). MS (ES+) m/e 195 [M+H]+.