Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:10][C:9]=2[CH:8]=[CH:7]1>CCOCC>[Cl:4][C:7]1[O:6][C:13]2[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:10][C:9]=2[CH:8]=1
Reactant: CCOC(=O)c1cc2occc2[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1cc2oc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
Under a N2 atmosphere, sulfuryl chloride (0.15 mL, 1.85 mmol) was added dropwise over 10 min to a stirring solution of ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (300 mg, 1.67 mmol) in ether (7.5 mL). The reaction was stirred at rt for 4 h. The solvent was removed in vacuo. The residue was taken up in DCM and washed with H2O (1×) and brine (1×), then dried with Na2SO4, filtered and concentrated. Purification by HPLC gave 160 mg of ethyl 2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylate. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.98 (s, 1H), 6.76 (s, 1H), 6.34 (s, 1H), 4.35 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH:12]([NH:16][C:17]([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=2[CH:22]=[N:23][N:24]4C(OC)=O)=[O:18])[CH2:11][CH2:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1(C([O-])=O)C2C(=CC=CC=2)C=N1>>[NH:24]1[C:25]2[C:21](=[C:20]([NH:19][C:17]([NH:16][CH:12]3[C:13]4[C:9](=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:15][CH:14]=4)[CH2:10][CH2:11]3)=[O:18])[CH:28]=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCc4cc(N5CCCCC5)ccc43)cccc21
Agent: O=C([O-])n1ncc2ccccc21
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCc2cc(N3CCCCC3)ccc21

Procedure:
The title compound was prepared using the procedure in Example 9, except using methyl 4-({[(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate instead of methyl 4-({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate. 1H NMR (DMSO-d6) δ 1.09 (t, 1.2H, Et2O), 1.40-2.20 (br m, 7H), 2.52-2.59 (m, 1H), 2.84-2.96 (m, 1H), 2.96-3.07 (m, 1H), 3.38 (q, 0.8H, Et2O), 3.52 (m, 4H), 5.24 (m, 1H), 5.76 (s, 0.2H, CH2Cl2), 7.05 (d, 1H), 7.21 (m, 1H), 7.33 (m, 1H), 7.50 (d, 1H), 7.65-7.77 (m, 3H), 8.29 (s, 1H), 9.15 (s, 1H); MS (ESI+) 376 (M+H)+; Elemental: Calculated for C22H25N5O.2HCl.0.1CH2Cl2-0.2Et2O: C58.31, H6.24, N14.85; Found: C58.22, H6.54, N15.00.
Reaction SMILES: [CH:1]1([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[CH:10]([CH:16]=O)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>O1CCCC1>[CH:1]1([N:8]2[CH2:9][CH:10]([CH2:16][N:21]([C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])[CH3:22])[C:11]([CH3:15])([CH3:14])[C:12]2=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNc1ccccc1F
Reactant: CC1(C)C(=O)N(C2CCCCCC2)CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CN(CC1CN(C2CCCCCC2)C(=O)C1(C)C)c1ccccc1F

Procedure:
A solution of Example 4A (30 mg, 0.12 mmoles), 2-fluoro-N-methylaniline (19 mg, 0.15 mmoles) MP-triacetoxyborohydride (137 mg, 0.3 mmoles) in tetrahydrofuran (1.25 mL) was stirred for twelve hours. The reaction was filtered and solvent evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% trifluoroacetic acid) over eighteen minutes at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 6.90-7.10 (m, 4H), 4.01-4.13 (m, 1H), 3.32 (dd, J=9.88, 7.50 Hz, 1H), 3.11-3.21 (m, 2H), 3.09 (t, J=9.36 Hz, 1H), 2.83 (s, 3H), 2.17-2.27 (m, 1H), 1.59-1.70 (m, 6H), 1.45-1.57 (m, 6H), 1.16 (s, 3H), 0.95 (s, 3H). MS (APCI+) m/z 347.2 (M+H)+.
Reaction SMILES: [I-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].O1CCCC1.[CH2:30]([O:37][CH2:38][CH:39]([CH3:48])[CH2:40]/[CH:41]=[CH:42]/[CH:43]([CH3:47])[CH2:44][CH:45]=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CCCCCC>[CH3:48][CH:39]([CH2:40][CH:41]=[CH:42][CH:43]([CH3:47])[CH2:44][CH:45]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:38][O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(/C=C/CC(C)COCc1ccccc1)CC=O
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C=CCC(C)C=CCC(C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1.52 g. (3.42 mmoles) of isobutyltriphenylphosphonium iodide in 30 ml. of anhydrous tetrahydrofuran was stirred and cooled to 0° C. while 1.55 ml. (3.42 mmoles) of n-butylithium solution in hexane was added. The resulting red solution was stirred for 10 minutes at room temperature then treated with a solution of rac. E-8-benzyloxy-3,7-dimethyl-4-octenal (0.594 g.; 2.28 mmoles) in 10 ml. of anydrous tetrahydrofuran. After stirring at room temperature for 30 minutes, the reaction mixture was treated with water and worked up by extraction with hexane as in Example 1. The semi-solid residue was treated with hexane and filtered to remove insoluble material. The filtrate was concentrated in vacuo to give 0.72 g. of yellow oil. This material was chromatographed on 30 g. of silica gel. Elution with 9:1 parts by volume hexane-ether afforded 0.427 g. (62.5%) of an oil. Evaporative distillation yielded rac. benzyl 2,6,10-trimethyl-undeca-4,8-dien-1-yl ether as a colorless liquid, b.p. 110°-115° C. (bath temperature) (0.03 mm Hg.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].S(OC)(O[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:34])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]

Procedure:
3-(4-chloro-3-ethoxycarbonylamino6-fluoro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.96 g) was stirred with dimethyl sulfate (0.72 ml) and potassium carbonate (0.33 g) in N,N-dimethylformamide (10 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated to give the title compound (1.1 g, oil).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:16]([OH:21])[C@:15]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2.[CH3:23][C:24](C)([O-])C.[K+]>[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:23]/[CH:24]=[C:10]1/[CH2:9][CH2:8][C@@H:7]2[C@:2]/1([CH3:1])[CH2:3][CH2:4][C@H:5]1[C@H:6]2[CH2:12][CH:13]=[C:14]2[C@:15]1([CH3:22])[C@@H:16]([OH:21])[CH2:17][C@H:18]([OH:20])[CH2:19]2
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12C(=CC[C@@H]3[C@@H]1CC[C@]1(C)C(=O)CC[C@@H]31)C[C@@H](O)C[C@@H]2O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C1/CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 9.12 g (30 mmol) of 1α-hydroxydehydroepiandrosterone and 25.1 g (60 mmol) of ethyltriphenylphosphonium iodide in 250 ml of tetrahydrofuran under a nitrogen atmosphere was added portionwise over ca. 5 min., 6.7 g (60 mmol) of potassium tert.-butoxide. The reaction temperature rose to 30°. After stirring at room temperature over night (16 hr.), the reaction was heated at reflux (oil bath) for 4.5 hr. to produce (Z)-1α,3β-pregna-5,17(20)-diene-1,3-diol (Tlc: EtOAc, showed starting material was consumed). On cooling to 50°, 60 ml of pyridine and 30 ml of acetic anhydride were added, and the reaction solution left stirring over night (18 hr.) and then heated at reflux for 2 hr. Acetylation was still incomplete (Tlc: 4:1, hexane--ethyl acetate showed mono and diacetates). Consequently, 100 mg of 4-dimethylaminopyridine was added, and heating at reflux was continued for 5 hr. Then, the reaction solution was diluted with 250 ml of 80% aqueous methanol (v/v) and, after cooling to room temperature, was extracted with 3×200 ml of hexane. The organic phases were washed in a countercurrent manner with 250 ml of 80% aq. methanol (v/v) and evaporated under reduced pressure to give 12.0 g of crude product. Chromatography on 500 g of silica gel prepared in hexane, and elution with 200 ml fractions of 8:1, hexane--ethyl acetate afforded, in fractions 7-11, 6.8 g of impure product and, in fractions 12-17, 4.2 g of pure product. The combined fractions 7-11, on rechromatography, gave 6.2 g of pure product. Thus, a total of 10.4 g (87%) of pure 1α,3β-diacetyloxypregna-5,17(20)-diene as an amorphous solid, was obtained as a 95:5 mixture of Z and E isomers, respectively. An analytical sample of (Z)-1α,3β-diacetyloxypregna-5,17(20)-diene, obtained by two recrystallizations from methanol, had mp 90°-91°.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:9][C:8](=O)[CH:7]1[CH2:6][CH2:5][CH2:4]2.[OH2:11].[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:3]12[CH2:9][C:8](=[CH:14][C:13]([O:12][CH2:16][CH3:15])=[O:11])[CH:7]1[CH2:6][CH2:5][CH2:4]2
Reactant: O
Reactant: C1CCOC1
Reactant: O=C1CC2CCCC12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CC2CCCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylphosphonoacetate (96.2 g; 429 mmol) was added to a suspension of 60% sodium hydride dispersion (16.5 g; 413 mmol) in tetrahydrofuran (480 mL) maintaining the temperature between 1–4° C. A solution of bicyclo[3.2.0]heptan-6-one (35.0 g; 318 mmol) in tetrahydrofuran (320 ml) was added maintaining the temperature between 5–15° C. The reaction mixture was stirred at ambient temperature overnight. Demineralised water (350 mL) added and the product was extracted with diethyl ether (3×450 ml). The combined organic phases were washed with brine (300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to leave a pale orange oil. This was purified by chromatography on a silica pad, eluting with 1:19 ethyl acetate:n-hexane. The product containing fractions were combined and concentrated in vacuo to yield the title compound as a colourless oil (47.8 g).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[OH:19][C:20]([CH3:25])([CH3:24])[C:21](=[O:23])[CH3:22].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl>O1CCCC1>[CH3:24][C:20]([O:19][Si:27]([CH3:30])([CH3:29])[CH3:26])([CH3:25])[C:21]([O:23][Si:27]([CH3:30])([CH3:29])[CH3:26])=[CH2:22]
Reactant: CC(=O)C(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(O[Si](C)(C)C)C(C)(C)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
A solution of 1.6M n-butyllithium/n-hexane solution (100 ml) was dropwise added to a solution of diisopropylamine (22.4 ml) in dry tetrahydrofuran (50 ml) at -10° C., and the mixture was stirred for 1 hour. A solution of 3-hydroxy-3-methyl-2-butanone (8 ml) in dry tetrahydrofuran (50 ml) was dropwise added at -10° C. and the mixture was stirred for 1 hour. Then, trimethylchlorosilane (20.4 ml) was dropwise added at -10° C. After stirring at 4° C overnight, the reaction mixture was filtered with celite and the solid was washed with diethyl ether (500 ml). The combined filtrate was washed with 1N hydrochloric acid (150 ml×2) and a saturated aqueous solution of NaHCO3 (150 ml×2), and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was distilled under reduced pressure to give 16 g of the title compound (bp=85°-90° C./20 mmHg) as colorless liquid (see Table 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[N:13]1([CH2:18][CH2:19]O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:13]1([CH2:18][CH2:19][O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCCN1CCCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc([N+](=O)[O-])cc1OCCN1CCCC1
Reaction time: 1 h
Yield: 61 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (1.5 g, 0.0088 mole), 1-pyrrolidineethanol (1.03 ml, 0.0088 mole) and triphenylphosphine (2.4 g, 0.0088 mole) in TBF (50 ml) at room temperature under argon was treated with diethyl azodicarboxylate (1.4 ml, 0.0088 mole). The reaction mixture was stirred for 1 h, then concentrated in vacuo and the residue treated with 2M HCl acid (50 ml) and ethyl acetate (50 ml). The mixture was shaken well, then the acid layer separated, washed with ethyl acetate (2×30 ml) and then basified by addition of potassium carbonate. The basic mixture was extracted with ethyl acetate (2×50 ml) and the combined extract dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow oil (1.43 g, 61%).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(=O)C.[Na+]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]([NH2:17])[S:16][C:2]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2C)cc1
Yield: 66.8 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 4 hours, followed by post-treatment to give a crude product, which was recrystallized with anhydrous ethanol to obtain a product as a white solid in a yield of 66.8%, mp: 139-140 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.37 (3H, s, ArCH3), 3.84 (3H, s, OCH3), 5.09 (2H, br, NH2), 6.93 (2H, d, J=8.68 Hz, ArH), 7.50 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 220.1 (M+, 100), 205.1 (18), 163.1 (31); HREI-MS Calcd. for C11H12N2OS: 220.0670. found: 220.0672. Anal. Calcd. for C11H12N2OS: C, 59.98; H, 5.49; N, 12.72. found: C, 59.90; H, 5.52; N, 12.55.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)(=O)=O.[Na+].[I-:26].O>C1COCC1.CC(C)=O>[Cl:16][C:11]1[CH:10]=[C:9]([C@H:8]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][CH2:6][I:26])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 364 (750 mg, 1.88 mmol) in THF (25 mL) and acetone (5 mL) at RT was added NaI (1411 mg, 9.41 mmol) and stirring was continued overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated to afford 810 mgs (100%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-iodopropylcarbamate (366).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[NH:12][C:11](=O)[O:10][C:8](=[O:9])[C:7]=12.C(N(CC)CC)C>CO>[NH2:12][C:6]1[C:5]([CH3:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: Cc1ccc(Cl)c2c(=O)oc(=O)[nH]c12
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(Cl)ccc(C)c1N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
At 22° C., 110 g (0.52 mol of 6-chloro-3-methylisatoic anhydride were introduced into a mixture of 750 ml of methanol and 47.6 g (0.47 mol) of triethylamine, and the mixture was then stirred at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in methylene chloride and extracted 3 times with 0.5 N aqueous sodium hydroxide solution. The mixture was dried over magnesium sulfate, filtered through silica gel and concentrated under reduced pressure, giving 45.5 g (43.8% of theory) of the title compound as a colorless oil with nD23=1.5765.
Reaction SMILES: CO[C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:8]([NH2:10])[CH3:9].C[O:12][C:13](=O)[CH2:14][C:15]([CH3:17])=O.S(=O)(=O)(O)O>O>[CH2:8]([N:10]1[C:13]([OH:12])=[CH:14][C:15]([CH3:17])=[C:4]([C:5]#[N:6])[C:3]1=[O:7])[CH3:9]
Reactant: CCN
Reactant: COC(=O)CC#N
Reactant: COC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCn1c(O)cc(C)c(C#N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
99 parts of cyanoacetic acid methyl ester are added at 5°-15° C. to 184.4 parts of a 49.4% strength aqueous solution of ethylamine, while stirring, stirring is continued for one hour, 133.5 parts of acetoacetic acid methyl ester are added and the mixture is heated at 100° C. for 5 hours in an autoclave, a pressure of 10.5 bars being generated. The reaction solution is then diluted with 600 parts of water and acidified with 74 parts of 61% strength sulphuric acid. The precipitated product is filtered off, washed and dried. This gives 153 parts (85.9% of theory) of 1-ethyl-3-cyano-4-methyl-6-hydroxypyrid-2-one with a melting point of 242°-45° C.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.[C:11]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH2:19][C:18]2=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: O=C1Cc2cccnc2N1c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1c(Cl)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
An ice-acetone cooled solution of anhydrous dimethylformamide (0.71 mL, 9.17 mmol) and anhydrous dichloromethane (1 mL) under a N2 atmosphere is treated drop-wise with phosphorus oxychloride (0.69 mL, 7.42 mmol). The resulting yellowish mixture is continued to stir for 30 mins to give an opaque gel. Crude 1-phenyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one is added portion wise as a solid over 10 minutes to form a red mixture. Further dichloromethane (1 mL) is added followed by pyridine (0.45 mL, 5.56 mmol) to give a dark red mixture. The reaction is allowed to warm slowly to room temperature over 1 hour, and stirred at room temperature for 38 hours. The red reaction mixture is concentrated, and the residue is treated with phosphorus oxychloride (8 mL) and the mixture heated in an oil bath at 110° C. for 3 hours. After concentration of the red mixture, the residue is treated with ice water, and treated with saturated aqueous sodium hydrogen carbonate solution until the effervescence ceases. The mixture is extracted with 5 portions of dichloromethane, the combined extracts are dried over magnesium sulfate, filtered and evaporated to leave an orange solid. The residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated, and after trituration with heptane gives 220 mg of 2-chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a fluffy pink solid (53% yield from 3,3-dibromo-1-phenyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one). MS: m/e 257/259 (M+H). 1H NMR (300 MHz, CDCl3): 10.24 (1H, s), 8.62 (1H, dd), 8.39 (1H, dd), 7.68-7.56 (3H, m), 7.49 (2H, d), 7.31 (1H, dd).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17](=[O:42])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:39][CH2:40][CH3:41])([CH3:15])([CH3:14])[CH3:13]>CC#N.CCOC(C)=O.O>[C:12]([O:16][C:17](=[O:42])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:1][CH:2]=[CH:3][CH3:4])[S:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)(=[O:30])=[O:31])=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:39][CH2:40][CH3:41])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC=CCBr
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC=CCN(c1ccc2c(c1)nc(CCC)n2CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Crotyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of 4-nitro-3-phenylbutanoic acid methyl ester, 138 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-phenylheptanedioic acid dimethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC)CCC.Cl[C:47]1[N:48]=[CH:49][C:50]2[CH:55]=[CH:54][NH:53][C:51]=2[N:52]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:47]3[N:48]=[CH:49][C:50]4[CH:55]=[CH:54][NH:53][C:51]=4[N:52]=3)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Reactant: Clc1ncc2cc[nH]c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: Fc1cnc2c(c1)c(-c1ncc3cc[nH]c3n1)nn2Cc1ccccc1F

Procedure:
Under an argon atmosphere, 2.000 g (5.389 mmol) of the compound from example 24A were dissolved in 200 ml of 1,4-dioxane, and 9.378 g (16.167 mmol) of hexabutyldistannane were added. Added to the mixture were 2.000 g (1.731 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.910 g (5.928 mmol) of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (described in Bioorg. Med. Chem. 17(19), 6926-6936; 2009). The mixture was heated to reflux for 60 h. After cooling, the reaction mixture was filtered through Celite and the filtrate was concentrated on a rotary evaporator. The residue was stirred successively with ethyl acetate, acetonitrile and dimethyl sulfoxide. Subsequently, the residue was dissolved in trifluoroacetic acid, and acetonitrile and water were added until slight turbidity. The mixture was filtered and the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. 161 mg (8% of theory) of the title compound were obtained.