Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].Br[C:21]1[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:24]=[C:25]([F:27])[CH:26]=1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[Na+].O>[F:27][C:25]1[CH:26]=[C:21]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:22]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:24]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(C(F)(F)F)c1
Temperature: -20 °C

Procedure:
To a solution of the commercially available benzyl {(2S)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (5.48 g, 20.58 mmol) and 3-bromo-5-fluorobenzotrifluoride (5 g, 20.58 mmol) in THF (52 ml) at −30° C. was added isopropylmagnesium chloride (20.58 ml, 41.2 mmol) dropwise under nitrogen. Removed the cold bath and allowed the reaction to age overnight to ambient temperature. The crude was cooled to −20° C. followed by addition of HC (1N, ice bath cold). The resulting mixture was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated. The pot residue was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40% ethyl acetate). Related fractions were pooled and evaporated under reduced pressure to afford a yellow oil of 5.4655 g as the titled compound. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.38-7.30 (m, 5H), 5.7 (d, J=7.5 Hz, 1H), 5.3 (ps quintet, J=7.5 Hz, 1H), 1.45 (d, J=7 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.O.O.[OH-].[Li+].Cl.[CH3:28][S:29](C)=O>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][O:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[S:29][CH3:28])[C:3]([OH:2])=[O:22]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccc(F)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
To a solution of 300 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-fluoro-benzoic acid methyl ester in 0.5 ml DMSO 70 mg NaSMe were added and stirred over night. After addition of 0.3 ml H2O and 20 mg lithium hydroxide monohydrate the solution was stirred for 5 h and then acidified with diluted HCl. The mixture was extracted with ethyl acetate, the organic layer dried over Na2SO4. Removal of the solvent yielded the acid as a yellow solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:33]=[CH:32][C:9]2[N:10]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:22])=[O:21])[C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4].Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>O.C1COCC1>[CH2:3]([O:5][C:6]1[CH:33]=[CH:32][C:9]2[N:10]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:35]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:36])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:21])=[O:22])[C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Reaction time: 5 h

Procedure:
0.29 g of NaOH pellets in 2 ml of water was added at 5° C., with stirring, to a solution of 1.1 g of 5-ethoxy-1,3-dihydro-1-(2-methoxy-4-aminobenzenesulfonyl)-3-cyclo-hexyl-2H-benzimidazol-2-one, obtained in Example 5 step B), in 25 ml of THF. 1 ml of phenyl chloroformate was then added with continued stirring. The reaction mixture was then stirred for 5 hours, the temperature being allowed to rise to 20° C. The mixture was then concentrated under vacuum, the residue was taken up with water, extracted with ether and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. 1 g of the expected product was obtained by crystallization from iso ether. M.p.=197° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1)[CH3:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: CCOC(OCC)N(C)C
Reactant: CCc1ccc2c(c1)C(=O)CCC2
Product: CCc1ccc2c(c1)C(=O)C(=CN(C)C)CC2

Procedure:
3,4-Dihydro-2-dimethylaminomethylene-7-ethyl-1(2H) naphthalenone was prepared from 7-ethyl-1-tetralone (5 g, 30.0 mmol) and N,N-dimethylformamide diethylacetal (15 ml) to give the compound as a yellow solid (4.6 g) m.p. 132-139°. δH (CDCl3) 7.87 (1H, d, J 1.7 Hz), 7.71 (1H, s), 7.21 (1H, dd, J 2.0, 7.7 Hz), 7.08 (1H, d, J 7.7 Hz), 3.11 (6H, s), 2.85 (4H, m), 2.66 (2H, q, J 7.6 Hz) and 1.24 (3H, m).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)([O-])=O.O>CS(C)=O>[O:7]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccccc2)s1
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
Phenol (3.3 g;, 35 mmol) is added in portions to a suspension of 60% NaH (1.3 g, 35 mmol) in DMSO (100 mL). The resulting mixture is stirred for 30 minutes then 5-nitrothiophene-2-carboxaldehyde (5 g, 32 mmol) is added. After 1 hour the reaction mixture is poured into water (1L) and washed with ether (4×500 mL). The combined organic layers are dried over Na2SO4, filtered and evaporated to dryness. The resulting material is dissolved in MeOH and passed through a column (2.5 cm×20 cm) of Amberjet 4400 (OH− form). The eluent is dried in vacuo then evaporated twice from CH3CN. The crude product is purified by column chromatography in EtOAc-hexanes (1:1) to yield the desired aldehyde (304 mg, 5%). 1H NMR (300 MHz, CDCl3) δ 6.52, 7.20, 7.27, 7.45, 7.55, 9.75.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([NH:60][CH2:61][CH2:62][NH2:63])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>C(Cl)(Cl)Cl.CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[NH:63][CH2:62][CH2:61][NH:60][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCNC(=O)OCc2ccccc2)CC1

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.10 g, 0.44 mmol), HATU (0.22 g, 0.57 mmol), DIPEA (0.38 mL, 2.2 mmol), N-Cbz-ethylenediamine (0.11 g, 0.57 mmol) and DMF (2 mL) to furnish the title compound as a yellow wax (170 mg, 96%), umax (CHCl3)/cm−1 3361, 3024, 2943, 1713, 1683, 1519, 1428, 1236, 1166; m/z (ESI) C21H32N3O5 requires 406.2337, found [M+H]+ 406.2330.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12]1)[CH:7]([CH3:9])[CH3:8].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:17]1([S:23]([N:15]2[CH:11]([O:10][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:12]=[CH:13][C:14]2=[O:16])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)COC1C=CC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)COC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
13.2 cm3 of a 1.6M solution of n-butyllithium in hexane is added to a solution cooled to -45° C. of 3.3 g of 1,5-dihydro-5-isobutyloxy-2H-pyrrol-2-one obtained at stage A, in 80 cm3 of tetrahydrofuran. The mixture is agitated for 30 minutes at -45° C./-40° C., then a solution of 3.74 g of benzenesulphonyl chloride in 12 cm3 of tetrahydrofuran is added. The temperature is allowed to return to the ambient over 2 hours. After evaporating to dryness, the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1--1), and 1.7 g of the expected product is obtained. m.p. 82°-83° C., crystallized from isopropanol.
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[C:11]([O:13]CC)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C:22]1=[O:27]>C(O)CO.CO>[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]2[C:3]3[CH2:8][CH2:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=3[C:11]([OH:13])=[C:23]2[C:22]1=[O:27]
Reactant: O=C1CNCCN1Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C1=C(OC)CCN(C)C1=O
Solvent: OCCO
Solvent: CO
Product: CN1CCc2c(c(O)c3n2CCN(Cc2ccc(F)c(Cl)c2)C3=O)C1=O
Temperature: 250 °C

Procedure:
A mixture of ethyl 4-methoxy-1-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carboxylate (0.27 g, 1.27 mmol) and 1-(3-chloro-4-fluorobenzyl)piperazin-2-one (0.92 g, 3.80 mmol) in ethylene glycol (2.5 mL) was heated in a sealed tube at 250° C. in a microwave reactor for 20 minutes with stirring. The resultant solution was diluted with methanol (2.5 mL) and cooled to 0° C. The white solid precipitate was filtered, washed successively with cold methanol and diethyl ether, and then dried under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][CH2:6][N:7]=[C:8]1[N:13]=[CH:12][C:11]([CH3:15])([CH3:14])[CH2:10][S:9]1.[CH2:20]([N:22]([CH2:25]C)CC)[CH3:21].ClCCl.C(Cl)(=[S:34])OCC>O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][CH2:6][N:7]=[C:8]1[N:13]([C:25](=[S:34])[NH:22][CH2:20][CH3:21])[CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][S:9]1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1CCN=C1N=CC(C)(C)CS1
Reactant: CCOC(=S)Cl
Solvent: O
Solvent: ClCCl
Product: CCNC(=S)N1CC(C)(C)CSC1=NCCc1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a mixture of 2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (0.28 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 3 minutes ethyl chlorothiocarbonate (0.15 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-methoxyphenethyl)imino-N-(ethylthiocarbamoyl)-5,5-dimethyl-1,3-thiazine (0.21 g, yield: 60%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C@@:11]34[C@@H:16]([O:17][C:4]=1[C:5]=23)[CH2:15][C@@H:14]([OH:18])[CH:13]=[CH:12]4.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH:29]1[CH2:38][C:37]2[C:32]3=[C:33]([CH2:39][C:40](=[O:41])[N:31]3[CH2:30]1)[CH:34]=[CH:35][CH:36]=2)=[O:28].C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[OH:18][C@H:14]1[CH:13]=[CH:12][C@@:11]23[CH2:10][CH2:9][N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH:29]4[CH2:38][C:37]5[C:32]6=[C:33]([CH2:39][C:40](=[O:41])[N:31]6[CH2:30]4)[CH:34]=[CH:35][CH:36]=5)=[O:28])[CH2:7][C:6]4=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:20]=[CH:19]4)[O:17][C@H:16]3[CH2:15]1
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCNC2
Reactant: O=C(CCCCCI)C1Cc2cccc3c2N(C1)C(=O)C3
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(CCCCCC(=O)C1Cc3cccc4c3N(C1)C(=O)C4)C2

Procedure:
Norgalanthamine (1.13 g, 1.64 mmol), 5-(6-iodo-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (1.50 g, 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3 mmol) are stirred in absolute chloroform (20 ml) for 54 hours at boiling temperature.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)cc21
Yield: 44.5 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (37 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (50 mgs) gave the title compound (35 mgs) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): 9.54 (s, 1H), 8.55 (d, J=8.4 Hz, 1H); 8.21 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.67-7.60 (m, 2H), 7.32-7.28 (m, 1H); 6.73 (s, 1H); 4.10-3.90 (broad abs., 2H), 3.93 (s, 3H); 3.29-3.25 (m, 1H), 2.70-2.40 (broad abs, 2H), 2.28-2.25 (m, 2H), 2.20-2.00 (broad abs, 2H); 1.33 (d, J=6.8 Hz, 6H), 1.16 (t, 7.1 Hz, 3H); LC/MS: (M+H)+ found 544.14; MP:195-197° C.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH3:21].O>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH2:19][CH2:20][CH3:21])[CH:7]=[O:8]
Reactant: CCCI
Reactant: COc1cc(C=O)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(I)cc(C=O)cc1OC
Temperature: 25 °C
Yield: 93.4 %

Procedure:
5-Iodovanillin (25 g, 0.09 mol) in DMF (100 mL) was treated with potassium carbonate (32 g, 0.23 mol) and n-propyl iodide (52 g. 0.3 mol, 31 mL) and heated for 16 hours. The solution was allowed to cool to room temperature and then poured into water (500 mL) and extracted with ether (3×250 mL). The organic layers were combined and washed with water and saturated sodium chloride solution, and then dried over magnesium sulfate. The organic layer was evaporated by distillation under diminished pressure to an oil, and then purified by column chromatography (silica, 7:3 petroleum ether-ethyl acetate), to provide an amber colored solid (26.9 g, 93%). 1H NMR (CDCl3) 1.07 (t, 3H), 1.85 (m, 2H), 3.89 (s, 3H), 4.06 (t, 3H), 7.39 (s, 1 H), 7.84 (s, 1 H), 9.81 (s, 1 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]2[S:19][C:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:21][C:14]=12.C(N(CC)CC)C>ClCCl>[CH:12]([C:13]1[CH:18]=[N:17][CH:16]=[C:15]2[S:19][C:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:21][C:14]=12)=[O:11]
Reactant: CC(C)(C)OC(=O)c1cc2c(CO)cncc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2c(C=O)cncc2s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
To a stirred solution of oxalyl chloride (0.10 mL, 1.17 mmol) in anhydrous dichloromethane (10 mL) at −78° C. was added DMSO (0.19 mL, 2.65 mmol). After 20 minutes, a solution of dimethylethyl 4-(hydroxymethyl)thieno[2,3-c]pyridine-2-carboxylate (0.28 g, 1.06 mmol) in anhydrous dichloromethane (4 mL) was added dropwise. The reaction was stirred 1 hours at −78° C. then treated with triethylamine (0.74 mL, 5.30 mmol). After 5 minutes, reaction was allowed to warm to room temperature over 30 minutes. The reaction was quenched with water (5 mL) and partitioned between dichoromethane (50 mL) and 50% sat. aq NaHCO3 (50 mL). The organic phase was washed with 50% sat. aq NaHCO3 (1×50 mL), dried (Na2SO4), filtered, and concentrated and dried in a desiccator to yield the title as a solid (0.25 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18](=[O:33])([O:26]C1C=CC=CC=1)[O:19]C1C=CC=CC=1.C(OC1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH3:9].[C:18]([OH:33])([OH:26])=[O:19]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C(Oc1ccccc1)c1ccccc1
Product: O=C(O)O
Temperature: 140 °C
Reaction time: 1 h

Procedure:
0.25 mol bisphenol A, 0.27 mol diphenyl carbonate 3.5×10-6 mol tetrabutyl ammonium bis-4-nitrobenzoate, 6×10-3 mol phenyl benzoate were added to the glass reactor flushed with nitrogen at room temperature. The temperature was increased to 140° C. in 11/2 hour duration. Later the pressure was reduced from atmosphere to 110 mm Hg and temperature increased to 240° C., and on maintenance of these conditions for 1 hour, about 85% phenol was collected. Subsequently, the temperature was increased to 270° C. and pressure reduced to 10 mm and under these conditions most of the phenol was collected in 2 hours. Finally, the reaction mixture was kept at 285° C. and 1 mm for 1 hour to remove traces of phenol. The polymer, bisphenol A polycarbonate obtained in 99% yield was white in color and its relative viscosity was 1.32.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:39]=[CH:38][C:28]([CH2:29][NH:30]C(=O)OC(C)(C)C)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40]>ClCCl.O1CCOCC1.CCOCC>[ClH:40].[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([CH2:29][NH2:30])=[CH:38][CH:39]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCc1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate (0.100 g) in dichloromethane (4 mL) was added 4.0 M HCl in dioxane (1 mL). The reaction was stirred at room temperature for 2 hours and then diluted with ether (20 mL). The product was removed by filtration under reduced pressure and dried to give (4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)methanamine hydrochloride as a bright yellow solid (0.085 g, 83% based on tris HCl salt). 1H NMR (DMSO-d6) 400 MHz δ 8.67 (br. s, 1 H), 8.42 (br. s, 3H), 8.13-8.10 (m, 1H), 7.98-7.95 (m, 1H), 7.51-7.42 (m, 4H), 7.39-7.38 (m, 1H), 7.35-7.26 (m, 5H), 7.15 (t, J=7.4 Hz, 1H), 6.93-6.90 (m, 1H), 6.78-6.73 (m, 1H), 4.06 (dd, JA=11.3 Hz, JB=5.9 Hz, 2H); LCMS: 416 [M+H]; Calc. for C27H21N5.3.26 HCl.0.12 dioxane.0.16 diethylether: C, 60.66; H, 4.86; N, 12.58. Found C, 60.66; H, 4.99; N, 12.58.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7])[CH3:2].[Br:10]Br.O=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH2:7][Br:10])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)CC(C)=O
Agent: O=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)CBr
Temperature: 25 °C
Reaction time: 60 h
Yield: 76.7 %

Procedure:
To a solution of 3-oxo-butyric acid ethyl ester (10.0 g, 78 mmol) in 100 mL of chloroform was added bromine (2.02 mL, 78 mmol) dropwise. The solution was stirred at room temperature for 60 hours without capping the flask (extended stirring at room temperature in an open system with oxygen flow facilitated the bromine migration from C-2 to C-4). The reaction mixture was partitioned between chloroform and water and the organic phase was dried over sodium sulfate. The organic solution was concentrated to provide 4-bromo-3-oxo-butyric acid ethyl ester (12.5 g, 45%). The crude product was taken on to the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:13][CH:12]2[N:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=3)[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:1].[C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[CH2:13]3)=[CH:16][CH:17]=1)#[N:26]
Reactant: N#Cc1ccc(N2C3CCC2CC(NC(=O)CCCl)C3)c2ccccc12
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)CCC(=O)NC1CC2CCC(C1)N2c1ccc(C#N)c2ccccc12
Product: Cl
Yield: 17.3 %

Procedure:
The title compound (16 mg, 19%) was synthesized in the same way as 165RL52 using 165RL50 (80 mg, 0.21 mmol), diethylamine (45 μL, 0.44 mmol), potassium carbonate (60 mg, 0.44 mmol) and acetonitrile (6 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[CH:15](Cl)C.S(Cl)(Cl)=O.CO.Cl>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:15][O:12][C:11]([C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:7]([OH:9])=[O:8])=[O:13]
Reactant: CC(Cl)Cl
Reactant: Cc1cc(C(=O)O)cc(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methylisophthalic acid (1.21 g, 6.5 mmol), dichloroethane (20 mL), DMF (3 drops), and thionyl chloride (2.42 g, 20 mmol) was heated to 80° C. for 4 hrs. The reaction was concentrated to dryness and a solution of MeOH (208 mg, 6.5 mmol) was added slowly and the reaction was stirred overnight at rt. 1 N Hydrochloric acid (10 mL) was added and reaction stirred for 1 hr. The pH was adjusted with sat'd sodium bicarbonate (50 mL) and the aqueous solution was extracted with methylene chloride to remove the diester. The aqueous portion was then acidified with 1 N HCl and extracted with methylene chloride/MeOH 95:5. The organic extracts were dried over sodium sulfate, filtered, concentrated, and the product was isolated via preparative reverse-phase HPLC.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[N:26]=[CH:25][CH:24]=[C:23]2[O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH:35]=O.O>O1CCCC1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[N:26]=[CH:25][CH:24]=[C:23]2[O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1/[CH:35]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(C)=C/c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
Sodium hydride (60 wt % oil, 52 mg) was dissolved in anhydrous tetrahydrofuran (1 ml), and a solution (0.5 ml) of triethyl 2-phosphonopropionate (119 mg) in tetrahydrofuran was added dropwise thereto under an argon atmosphere at 0° C. The mixture was stirred at 0° C. for 30 min, and a solution (0.5 ml) of 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (100 mg) in tetrahydrofuran was then added dropwise thereto. The reaction mixture was stirred at room temperature for one hr, and water (1 ml) was then added dropwise to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (64 mg, yield 50%).