Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][NH:3]1.Cl[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19].C(OCC)(=O)C.O=C1NCCCN1NC(=O)OCC1C=CC=CC=1.[OH:48][C:49]1[C:50](=[O:68])[CH:51]=[C:52]([C:55]([NH:57][N:58]2[CH2:63][CH2:62][CH2:61][N:60]([C:64]([NH2:66])=[O:65])[C:59]2=[O:67])=[O:56])[NH:53][CH:54]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F>C(OCC)(=O)C.O.ClCCl>[OH:48][C:49]1[C:50](=[O:68])[CH:51]=[C:52]([C:55]([NH:57][N:58]2[CH2:63][CH2:62][CH2:61][N:60]([C:64]([NH:66][S:18]([NH:21][C:22]([N:3]3[CH2:4][C@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:2]3=[O:1])=[O:23])(=[O:20])=[O:19])=[O:65])[C:59]2=[O:67])=[O:56])[NH:53][CH:54]=1
Reactant: NC(=O)N1CCCN(NC(=O)c2cc(=O)c(O)c[nH]2)C1=O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: O=C(NN1CCCNC1=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O)OCc1ccccc1
Yield: 55.2 %

Procedure:
To a suspension of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (6.61 g, 30.0 mmol) in 300 ml ethyl acetate chlorosulfonyl isocyanate (4.25 g, 30.0 mmol) was added, and the mixture was stirred for 1 hour at room temperature (solution A). To a solution of 3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-carbonyl]-amino]tetrahydro-2-oxo-1(2H)-pyrimidinecarboxamide (8.86 g, 30.0 mmol) in 300 ml ethyl acetate, N-methyl-N-trimethylsilyltrifluoroacetamide (23.91 g, 120 mmol) was added. After 30 minutes a clear solution was obtained; 300 ml dichloromethane was added, followed by the dropwise addition of solution A at 0° C. After stirring overnight at room temperature 300 ml water was added whereupon an oily residue separated. The solvents were decanted off and the residue triturated with ether to give 10.27 g of the desired product (crude). The product was suspended in water and the pH adjusted to 6 with 2N sodium hydroxide. After freeze drying of the resulting solution the product was chromatographed in four portions on XAD under mplc conditions with water and water:acetonitrile 9:1 as eluents. The product-containing fractions were freeze dried to give a total of 5.2 g of the desired product.
Reaction SMILES: N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:25]I.[C:27]([O:31][C:32](=[O:42])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:42])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1CI
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (2.6 g, 37 mmol) and PPh3 (9.6 g, 37 mmol) in DCM (180 mL) is slowly added I2 (9.4 g, 37 mmol) over a period of 10 min. The mixture is stirred at ambient temperature for 30 min. Then a solution of (2-hydroxymethylphenyl)-carbamic acid tert-butyl ester (7.5 g, 33.6 mmol) in DCM (40 mL) is added dropwise. The mixture is stirred at ambient temperature for 1 h, then is concentrated to about 70 mL and the resulting precipitate is filtered and washed with DCM. The filtrate is concentrated and purified to give the title compound as a solid.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[OH-].[K+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.O>CN(C=O)C>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:1]2[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]2=[O:8])=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: O=C1CCCC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) mixture of commercially available piperidine-2,6-dione (400 mg; 3.46 mmol; 1.0 equiv.) and KOH (213 mg; 3.81 mmol; 1.1 equiv.) in anh. DMF (3.5 ml) was stirred, under nitrogen, for 30 min., and was then treated with a solution of commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene (956 mg; 3.63 mmol; 1.05 equiv.) in anh. DMF (1 ml). The resulting mixture was further stirred at rt, under nitrogen, for 3 days. Water was added, and the mixture was extracted with Et2O (3×). The mixed organic layers were washed successively with 2 M aq. NaOH, aq. sat. NH4Cl, and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 1-(4-(trifluoromethoxy)benzyl)piperidine-2,6-dione as a colorless oil. LC-MS (conditions E): tR=0.67 min.; no ionisation.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([O:26][C:27](=[O:32])[CH2:28][N:29]=[C:30]=[O:31])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][N:29]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:30]1=[O:31])[CH3:25]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CCOC(=O)CN=C=O
Product: CCOC(=O)Cn1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=O
Yield: 60.4 %

Procedure:
(1-Cyclopentyl-7-methoxy-2,4-dioxo-1,4-dihydro-2H-pyrimido[5,4-c]quinolin-3-yl)-acetic acid ethyl ester (24 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and isocyanato-acetic acid ethyl ester (0.5 mmol) following general procedure C. LCMS: m/z 398 [M+1]+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.C(O)(C)C.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CCC(=O)O)cc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
Sodium hydroxide (61 mg) was added to a solution of ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D114) (68 mg) in THF (5 mL), isopropanol (5 mL) and water (2.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoic acid (E89) (6 mg). δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.69 (2H, t), 2.98 (2H, t), 4.97 (1H, m), 6.33 (1H, s), 7.44 (1H, d), 7.55 (1H, d), 7.75 (1H, dd), 8.21 (1H, s), 8.40 (1H, dd), 8.49 (1H, d), 11.34 (1H, s), 12.25 (1H, s); MS (ES): C23H20N4O4 requires 416; found 417.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]([C@@:24]1([OH:65])[CH2:41][C@H:40]([O:42][C@@H:43]2[O:57][C@@H:56]([CH3:58])[C@H:46]3[O:47][C@H:48]4[N:53]([C@H:45]3[CH2:44]2)[CH2:52][CH2:51][O:50][C@@H:49]4[O:54][CH3:55])[C:39]2[C:26](=[C:27]([OH:64])[C:28]3[C:29](=[O:63])[C:30]4[C:35]([C:36](=O)[C:37]=3[C:38]=2[OH:59])=[C:34]([O:61][CH3:62])[CH:33]=[CH:32][CH:31]=4)[CH2:25]1)[CH2:3][O:4][CH:5]1[O:10][CH:9]([CH2:11][O:12][CH2:13][C:14]([O:16]N2C(=O)CCC2=O)=O)[CH2:8][CH2:7][CH2:6]1.F[C:67](F)(F)C(O)=O.[NH2:73][CH2:74][CH2:75][N:76]1[C:80](=[O:81])[CH:79]=[CH:78][C:77]1=[O:82].C(N(CC)CC)C>ClCCl>[O:82]=[C:77]1[CH:78]=[CH:79][C:80](=[O:81])[N:76]1[CH2:75][CH2:74][NH:73][C:14](=[O:16])[CH2:13][O:12][CH2:11][CH:9]1[CH2:8][CH2:7][CH2:6][CH:5]([O:4][CH2:3][C:2](=[O:1])[C@@:24]2([OH:65])[CH2:41][C@H:40]([O:42][C@@H:43]3[O:57][C@@H:56]([CH3:58])[C@H:46]4[O:47][C@H:48]5[N:53]([C@H:45]4[CH2:44]3)[CH2:52][CH2:51][O:50][C@@H:49]5[O:54][CH3:55])[C:39]3[C:26](=[C:27]([OH:64])[C:28]4[C:29](=[O:63])[C:30]5[C:35]([C:36](=[CH2:67])[C:37]=4[C:38]=3[OH:59])=[C:34]([O:61][CH3:62])[CH:33]=[CH:32][CH:31]=5)[CH2:25]2)[O:10]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1CCCC(COCC(=O)ON2C(=O)CCC2=O)O1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: NCCN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1c2c(OC)cccc2C(=O)c2c(O)c3c(c(O)c21)[C@@H](O[C@H]1C[C@H]2[C@H](O[C@@H]4[C@@H](OC)OCCN42)[C@H](C)O1)C[C@](O)(C(=O)COC1CCCC(COCC(=O)NCCN2C(=O)C=CC2=O)O1)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude intermediate 50 (103.8 mg) in anhydrous dichloromethane (29.7 ml) under argon atmosphere, the commercially available N-(2-aminoethyl)maleimide trifluoroacetate salt (57.9 mg, 0.228 mmol) and anhydrous triethylamine (23.1 mg, 0.228 mmol) were added. The reaction mixture was stirred at room temperature for 1 h, until disappearance of the starting material (HPLC-MS analysis). The solvent was evaporated under vacuum and the residue rinsed with a mixture of Et2O/n-hexane (1 ml/20 ml). The crude was then purified by flash column chromatography (EtOH:CH2Cl2=0.2:9.8) on silica gel (230-400 mesh), affording 12.2 mg (red solid, yield calculated on PNU-159682=20%) of 51 as a diasteroisomeric mixture. MS (ESI): 936 [M+H]+. Retention time=5.86, according to the following method:
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1.[Na].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: OCc1ccc(O)cn1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: OCc1ccc(OCc2cccc(Cl)c2)cn1
Reaction time: 0.42 h

Procedure:
The solution of 16.2 g of 5-hydroxy-2-pyridinemethanol hydrochloride in 150 ml of methanol is added to a solution of 4.6 g of sodium in 250 ml of methanol, while stirring, over a period of 25 minutes. The solution is stirred for one hour and then a solution of 19.3 g of m-chlorobenzyl chloride in 50 ml of methanol is added. Then the mixture is refluxed for 19 hours, cooled, filtered and the filtrate evaporated to a residue. The residue is suspended in 100 ml of water, made basic with 20% aqueous sodium hydroxide solution and then extracted with chloroform. The chloroform extract is separated, dried over sodium sulfate, filtered and the filtrate evaporated, to yield 5-(m-chlorobenzyloxy)-2-pyridinemethanol melting at 78°-80°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)C(O)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:27]=1)=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2cccc(Oc3ccccc3)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 3-phenoxybenzoic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 94% purity by HPLC. MS(ESI+): m/z=474.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][O:39][CH:40]=2)O1>C([O-])(=O)C.[K+].C(#N)C.C(Cl)Cl.CO>[O:39]1[CH:40]=[C:36]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:37]=[N:38]1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: c1cc(-c2cnc3[nH]c4cnc(-c5cnoc5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 85 °C
Yield: 13.6 %

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (130 mg, 0.18 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (140 mg, 0.74 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18 mg, 0.002 mmol) in 1N aqueous potassium acetate solution (0.62 mL) and acetonitrile (3 mL) was heated under microwave irradiation at 85° C. for 18 minutes. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative HPLC [0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min] to afford the title compound as a beige solid (10 mg, 10%). 1H NMR (DMSO-D6, 400 MHz): 12.32 (s, 1H), 9.47 (s, 1H), 9.18 (s, 1H), 8.95 (s, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.2 Hz, 1H), 8.68 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=6.55 min, M+H+=410.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(OCC)(=O)C>[Cl-:7].[CH2:12]([O:11][C:9]([CH2:8][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)CCl
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[n+]1ccccc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
Pyridine (1 equivalent) and ethyl chloroacetate (1 equivalent) in ethyl acetate were heated (70° C.) for 24 hours. The reaction mixture was cooled to room temperature and the resulting crystalline pyridinium salt filtered, washed with ethyl acetate, and dried in vacuum.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:36]2[C:37]([O:42][CH2:43][CH3:44])=[N:38][CH:39]=[CH:40][CH:41]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])(=[O:24])=[O:23])[C:13]1=[O:35]>ClCCl.N1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])(=[O:23])=[O:24])[C:13](=[O:35])[C:12]2([NH:11][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:36]1[C:37]([O:42][CH2:43][CH3:44])=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
0.83 ml (6.6 mmol) of phenyl chloroformate was slowly added dropwise to a solution, cooled to 0° C., of 2.57 g (5.1 mmol) of 3-amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 10 ml of dichloromethane and 4.1 ml of pyridine. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in a little dichloromethane, and six times the volume of diisopropyl ether were added. The resulting precipitate was filtered off, washed with diisopropyl ether and dried in vacuo. 3.01 g of the title compound were obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][PH:21](=[O:25])[O:22][CH2:23][CH3:24]>C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]([P:21]([CH3:20])(=[O:25])[O:22][CH2:23][CH3:24])[OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO[PH](C)=O
Reactant: CC(C)(C)OC(=O)NCC(C=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 1.46 g of 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-propionaldehyde, 0.54 g of ethyl methylphosphinate and 0.695 ml of triethylamine is heated to 100° for 2 hours. The reaction mixture is cooled to room temperature and chromatographed on silica gel to give ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxypropyl(methyl)phosphinate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1.Cl.C(OCC)C>CC(O)C>[ClH:1].[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][CH3:14])=[O:12])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)(=[O:32])[CH3:31]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(NC(C)=O)cc2)ncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 71.2 %

Procedure:
To a mixture of 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]-N-methylbenzamide (54 mg, 0.178 mmol) and N-(4-aminophenyl)acetamide (28 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for 30 hours. After the reaction was cooled to room temperature the mixture was filtered, and the solid was washed with 2-propanol, hexane, and ethyl acetate. The solid was then dried under vacuum to give 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]-N-methylbenzamide hydrochloride (58 mg, 71%) as a yellow tan solid. 1H NMR (DMSO-d6/D2O): δ 9.05 (s, 1H), 8.20 (m, 1H), 7.59 (d, 1 H), 7.40-7.50 (m, 5 H), 7.24 (t, 1 H), 2.76 (s, 3 H), 2.02 (s, 3H). MS m/z 421 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[Mg].S(=O)(=O)(O)O>CCOCC>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][CH:8]=[CH:9][C:10]=1[C:4]([OH:6])([CH3:5])[CH2:3][CH2:2][OH:1]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)CCO
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
0.44 g. of 1-hydroxy-3-butanone in 40 ml. of ether is added dropwise at 20°, with stirring, to a Grignard solution prepared from 2.33 g. of 4-bromobiphenyl and 0.24 g. of magnesium in 100 ml. of ether. The mixture is stirred for a further two hours, the resulting alcoholate is decomposed by means of dilute sulfuric acid, and standard working up gives 3-p-biphenylyl-1,3-butane-diol, m.p. 115°-117°.
Reaction SMILES: [O:1]1[CH2:18][C@@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@H]3CO3)c12
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(CNC[C@@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
To a solution of (R)-(−)-4-(2,3-Epoxypropoxy)-carbazole (7 g, 0.029 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (8.7 mL, 0.058 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was concentrated to half its volume, and cooled to room temperature to give a colorless solid. The solid was filtered, re-dissolved in EtOAc (60 mL) by refluxing, concentrated to 40 mL and the colorless precipitate formed on cooling to room temperature, was filtered and dried. Recrystallization of the residue obtained from the filtrate was repeated until maximum amount of the solid was recovered. The combined solid was triturated with diethylether by stirring for 6 hours, followed by filtration to afford 5.5 g (46% yield) of the desired compound as a colorless solid with m.p: 152-153° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.86-2.92 (m, 1H), 2.99-3.02 (m, 1H), 3.74-3.86 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.44 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.41 (m, 4H), 8.09 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.99%
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([CH3:11])[C:5]([CH3:12])=[C:4]([C:13](O)=[O:14])[C:3]=1[CH3:16].S(Cl)([Cl:19])=O.S(=O)=O.[ClH:24]>>[CH3:1][C:2]1[C:7]([C:8]([Cl:24])=[O:9])=[C:6]([CH3:11])[C:5]([CH3:12])=[C:4]([C:13]([Cl:19])=[O:14])[C:3]=1[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C)c(C(=O)O)c(C)c(C)c1C(=O)O
Reactant: Cl
Agent: O=S=O
Product: Cc1c(C)c(C(=O)Cl)c(C)c(C)c1C(=O)Cl

Procedure:
To a 500 ml. three-necked flask equipped with stirrer, reflux condenser and nitrogen inlet is added 100 grams tetramethylterephthalic acid and 200 ml. thionyl chloride. The mixture is stirred at reflux of 6 hours during which time the acid dissolves and a mixture of sulfur dioxide and hydrogen chloride is evolved. At the end of this period the excess thionyl chloride is removed by distillation. The crude tetramethylterephthaloyl chloride is recrystallized twice from cyclohexane.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][N:10]2[C:22]3[C:21]4[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:15]=3)=[CH:7][CH:6]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O>CN(C=O)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[C:22]3[N:10]([CH2:9][C:8]4[CH:37]=[CH:38][C:5]([O:4][CH2:3][CH2:2][N:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:6][CH:7]=4)[C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:20]=2[CH:26]=1)=[CH:15][C:14]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:13][CH:12]=4
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 65 °C

Procedure:
Intermediate #18, 11-[4-(2-Chloroethoxy)-benzyl]-8-benzyloxy-3-methoxy-5,11-dihydro-6H-benzo[a]carbazole, (6 g, 11.5 mmol) in DMF was treated with KI (2.5 g, 15.0 mmol) and piperidine (12 mL) and heated to 65° C. for 18 hours. The reaction was worked up by pouring the crude reaction mixture into water and extracting with ethyl acetate. The ethyl acetate layer was washed with NaHCO3 aq., brine and dried over MgSO4. The resultant was chromatographed on silica gel using CH2Cl2 (100%), CH2Cl2 :MeOH (98:2), CH2Cl2 :MeOH (96:4) as the eluting solvents. The product (3.2 g) was isolated as an oil: 1H NMR (DMSO) 7.52-7.12 (m, 8 H), 6.98-6.82 (m, 5 H), 6.80 (dd, 1 H, J=8.4 Hz, 2.6 Hz), 6.73 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 5.56 (s, 2 H), 5.11 (s, 2 H), 3.98 (t, 2 H, J=6.0 Hz), 3.70 (s, 3 H), 2.85-278 (m, 2 H), 2.75 (s, 2 H), 2.60 (t, 2 H, J=6.5 Hz), 2.42-2.38 (m, 4 H), 1.70-158 (m, 4 H), 1.58-1.35 (m, 2 H).