Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][N:7]1C[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.CO>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:29])=[CH:20][CH:19]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CCCN1CCCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CO
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Yield: 77 %

Procedure:
A slurry of 4-{(R)-2-[4-(4-chloro-benzyl)-phenoxymethyl]-piperidin-1-yl}-butyric acid methyl ester (570 mg, 1.42 mmol) in 4:1 methanol:water (6 mL) was stirred at 50° C. for 18 h. The solvent was removed in vacuo. The mixture was diluted with water (25 mL), brought to pH 7 with 2N HCl and extracted with ethyl acetate (100 mL). The aqueous layer was re-extracted with ethyl acetate (1×80 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the title product as a white solid (424 mg, 77%); HPLC 99.2%; 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.70 (m, 5H), 1.89-1.94 (m, 1H), 2.17-2.26 (m, 3H), 2.33-2.38 (m, 1H), 2.77-2.87 (m, 2H), 3.02-3.07 (m, 1H), 3.70-3.74 (dd, 1H J1=6.4 Hz, J2=10.8 Hz), 3.84-3.88 (m, 1H), 3.856 (s, 2H), 6.84 (d, 2H, J=8.8 Hz), 7.11 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.4 Hz); 7.32 (d, 2H, J=8.4 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[OH-].[Na+].OP([O-])(O)=O.[K+]>CC(C)=O.CC#N.CO.O>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:16]=[C:15]([NH:22][CH:19]2[CH2:21][CH2:20]2)[N:14]=1
Reactant: NC1CC1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC#N
Product: COc1ccc(Nc2nc(Cl)nc(NC3CC3)n2)cc1Cl

Procedure:
To 101 (2.01 g, 6.5 mmol) dissolved in acetone (35 mL) was added a solution of cyclopropylamine (0.45 mL, 6.5 mmol) in acetone (5 mL) followed by addition of NaOH (2.6 mL, 2.5 N, 7.0 mmol) and 6.5 mL of water. The reaction mixture was stirred and heated at reflux for 3 hours. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The sample was filtered, concentrated, and dried overnight under vacuum. Column chromatography (50:50 v:v hexane:ethyl acetate) yielded a faint yellow solid (E13) (1.12 g, 53%); mp 172° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 [KH2PO4 (0.01 M, pH 3.2): CH3OH:CH3CN], 264 nm, Rt 24.6 min, 99% purity; MS (TOF ES+) m/z 328 (72.6), 326 (M+H, 100).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH:24]([C:31]([F:34])([F:33])[F:32])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH:24]([C:31]([F:33])([F:34])[F:32])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)-c1ccncc1C(C(F)(F)F)O2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)COc1cc2c(cc1Br)-c1ccncc1C(C(F)(F)F)O2
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((9-bromo-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.092 mmol) in dichloromethane (10 mL) at room temperature was added TFA (0.035 mL, 0.458 mmol) and stirred overnight. The solvent was removed under reduced pressure to afford a residue which was purified by preparative HPLC using 0.1% TFA in MeOH. The purification afforded (2S)-1-((9-bromo-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (15 mg, 0.033 mmol, 36% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.64 (m, 1H), 8.54 (m, 1H), 8.23 (m, 1H), 7.88 (s, 1H), 6.91 (s, 1H), 6.10 (m, 1H), 4.3 (m, 1H), 4.12 (m, 1H), 3.52 (m, 1H), 1.85 (m, 1H), 1.72-1.69 (m, 1H), 1.61-1.56 (m, 1H), 1.05 (m, 6H). LCMS (ESI) m/e 445.2 [(M+H)+, calcd for C19H21BrF3N2O2 445.1]; LC/MS retention time (Method C): tR=1.74 min; HPLC retention time (method A): tR=5.66 min, 5.75 min (diastereomeric mixture); HPLC retention time (method B): tR=6.27 min, 6.34 min (diastereomeric mixture).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:23]=[C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[C:14]([CH2:15][OH:16])[N:9]2[N:8]=1)=[O:5])[CH3:2]>C1COCC1.O=[Mn]=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:23]=[C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=[C:14]([CH:15]=[O:16])[N:9]2[N:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(CO)n2n1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C=O)n2n1

Procedure:
The product of Step 1 (154 mg, 0.50 mmol) was dissolved in THF (50 mL), to which was added MnO2 (250 mg). This mixture was heated at reflux for 18 h., at which point two further portions (50 mg each) were added over the next 8 hours. Finally, the mixture was heated at reflux for 18 h., allowed to cool, then the MnO2 removed by filtration over celite which was washed with THF and MeOH/CH2Cl2. The solvent was removed under reduced pressure to afford 1-ethyl-3-(5-formyl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-urea as a crude solid. LCMS (APCI+) 311.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([OH:23])=O)=[C:16]([O:19][CH3:20])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[O:23])=[C:16]([O:19][CH3:20])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OC(C)(C)C
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: COc1cc2c(cc1C(=O)Nc1ccncc1)SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 74.6 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-methoxythiochromane-7-carboxylic acid (300 mg), 4-aminopyridine (83.3 mg) and 2-chloro-1-methylpyridinium iodide (271 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-methoxy-N-(4-pyridyl)thiochromane-7-carboxamide (274 mg) was obtained as a pale-red amorphous solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([C:34]1([O:37]C(=O)C)[CH2:36][CH2:35]1)=[O:33]>>[OH:37][C:34]1([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH2:27][CH:28]5[CH2:29][CH2:30]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:33])[CH2:36][CH2:35]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CCN(CC)CC.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C(Cl)Cl>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:17](=[O:20])[CH2:18][CH3:19])=[O:5]
Reactant: Nc1ccccc1C=O
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.6 %

Procedure:
To a solution of 2-aminobenzaldehyde (1 g, 8.26 mmol) and Et3N (1.15 ml, 8.26 mmol) in DCM (50 ml) was added propionyl chloride (0.72 ml, 8.26 mmol) and the resulting mixture stirred at RT for 3 days. The mixture washed with water, sat. NaCl, dried over MgSO4, filtered and evaporated to afford the title compound 1.4 g (96%). 1H NMR (CDCl3): 1.30 (t, J 7.6 Hz, 3H), 2.51 (q, J 7.6 Hz, 2H), 7.23 (m, 1H), 7.62 (m, 1H), 7.69 (m, 1H), 8.78 (m, 1H), 9.94 (s, 1H), 11.19 (brs, 1H).
Reaction SMILES: [Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C.[CH2:46]([O:53][C:54]1[C:55]([C:77]([OH:79])=O)=[N:56][C:57]([CH2:61][C:62]2([C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)=[N:58][C:59]=1[OH:60])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[Si:80]([O:87][CH2:88][CH2:89][NH:90][CH:91]([CH3:93])[CH3:92])([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81]>>[CH2:46]([O:53][C:54]1[C:55]([C:77]([N:90]([CH2:89][CH2:88][O:87][Si:80]([C:83]([CH3:85])([CH3:84])[CH3:86])([CH3:81])[CH3:82])[CH:91]([CH3:92])[CH3:93])=[O:79])=[N:56][C:57]([CH2:61][C:62]2([C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)=[N:58][C:59]=1[OH:60])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared by following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[Br:21]C(Br)(F)C(F)(F)F>O1CCCC1>[Br:21][CH:13]1[CH2:12][CH:11]1[O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:14])([F:15])[F:1])=[CH:9][CH:8]=1
Reactant: FC(F)(F)Oc1ccc(OC2CC2)cc1
Reactant: FC(F)(F)C(F)(Br)Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(OC2CC2Br)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
4-(Trifluoromethoxy)cyclopropoxybenzene (3 g) was dissolved in tetrahydrofuran (100 ml) and the solution was cooled to −78° C. under a nitrogen atmosphere. tert-Butyllithium (22.9 ml, 1.5M in pentane) was added dropwise and the solution was stirred for 3 hours. Dibromotetrafluoroethane (8.2 ml) was added dropwise and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched by the dropwise addition of water (50 ml). The product was extracted with diethyl ether. The combined organic fractions were dried (brine, MgSO4) and concentrated in vacuo. The residue was purified on silica using hexane as eluant, to yield the product as a colourless oil (2.2 g). 1H NMR (360 MHz, CDCl3) δ 0.86 (4H, m), 3.79 (1H, m), 7.15 (1H, dd, J 8.9, 2.7 Hz), 7.24 (1H, d, J 8.9 Hz), 7.42 (1H, d, J 2.7 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][CH:23]=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu](I)I.O1CCOCC1>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:9]2[CH2:8][C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:10]2=[O:14])=[CH:22][CH:23]=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc2c(c1)CNC2=O
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Temperature: 105 °C
Yield: 44.1 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer was purged with nitrogen and charged with 102c (570 mg, 3.02 mmol), 102d (1.85 g, 6.04 mmol), cesium carbonate (1.96 g, 6.04 mmol), N,N′-dimethyl-ethylenediamine (266 mg, 3.02 mmol), and 1,4-dioxane (27 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (287 mg, 1.51 mmol) was added, and the reaction mixture was heated at 105° C. (oil bath temperature) for 14 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 50% ethyl acetate/hexanes) to afford a 41% yield (555 mg) of 102e as an off-white solid: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ 7.86 (d, 1H, J=8.1 Hz), 7.66 (dd, 1H, J=7.9, 1.5 Hz), 7.59 (dd, 1H, J=8.1, 1.5 Hz), 7.52 (s, 1H), 7.29 (m, 2H), 5.20 (s, 2H), 4.77 (s, 2H), 1.99 (s, 3H), 1.40 (s, 9H); MS (ESI+) m/z 416.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[CH:26]=[N:25][N:24]=[N:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH2:20][O:21][C:30]3[CH:31]=[CH:32][C:27]([N:22]4[CH:26]=[N:25][N:24]=[N:23]4)=[CH:28][CH:29]=3)=[C:17]([CH3:19])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1CO
Reactant: Oc1ccc(-n2cnnn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1COc1ccc(-n2cnnn2)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.2 mmol) in THF (6.4 mL) was added, 4-tetrazol-1-yl-phenol (0.52 g, 3.2 mmol), polymer bound triphenylphosphine (3 mmol/g, 1.6 g). To this solution was added ditertierybutylazodicarboxylate (1.1 g, 4.8 mmol), stirred for 4 hours and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography to provide the desired product. 1H NMR (CDCl3): δ 9.01 (1H, s), 7.66 (2H, d), 7.15 (2H, d), 5.21 (2H, s), 4.19 (2H, m), 3.10 (1H, m), 2.86 (2H, m), 2.45 (3H, s), 2.08 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].OS(O)(=O)=O.[N+:16]([O-])([OH:18])=[O:17]>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([N+:16]([O-:18])=[O:17])[C:3]=1[F:10]
Reactant: O=[N+]([O-])O
Reactant: Fc1cc(F)c(Br)c(F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(F)c(Br)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a cooled (1.3° C.) mixture of 1-bromo-2,4,6-trifluorobenzene (30.0 g, 142 mmol) and H2SO4 (115 mL) was added HNO3 (68%, 102 mL) over 1.5 h at such a rate that the internal temperature was <8° C. After stirring at 0° C. for 2 h, the resulting mixture was poured into ice water (1850 mL), stirred vigorously for 30 min and extracted with CH2Cl2 (3×600 mL). The combined organic layers were washed with water (2×600 mL), dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a clear yellow oil (35.0 g, 99% yield). 1H NMR (CDCl3) δ 7.01 (ddd, J=2.4, 7.8, 9.3 Hz, 1H); 19F NMR (CDCl3) δ −116.20 to −116.10, −107.73 to −107.71, −93.80 to −93.70.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][C:15]=2[F:24])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: CNC(=O)c1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1

Procedure:
2,3,4-Trifluorobenzoic acid and 4-amino-3-fluoro-N-methylbenzamide [Anker et al, Helv. Chim. Acta., 67(3), 706-716 (1984)] were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, followed by purification by chromatography on silica gel (100% EtOAc as eluant), 3,4-difluoro-2-{2-fluoro-4-[(methylamino)carbonyl]anilino}-benzoic acid was isolated as a pale, yellow-orange solid; m.p. (EtOAc/MeOH) 242-244° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.70 (v br s, 1 H), 9.28 (br s, 1 H), 8.36 (br d, J=4.5 Hz, 1 H), 7.88-7.80 (m, 1 H) 7.69 (dd, J=12.5, 1.7 Hz, 1 H), 7.60 (dd, J=8.5, 1.5 Hz, 1 H), 7.19 (dd, J=16.7, 9.3 Hz, 1 H), 7.01 (ddd, J=8.6, 8.6, 5.8 Hz, 1 H), 2.77 (d, J=4.4 Hz, 3 H). Anal. calcd. for C15H11F3N2O3: C, 55.6; H, 3.4; N, 8.6. Await Found.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([CH3:11])[CH:3]=1.[OH-].[Na+].[CH2:14](I)[CH3:15]>C1COCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:14][CH3:15])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)cc2[nH]ncc12
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ncc2c(C)cc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of 6-bromo-4-methyl-1H-indazole (1000 mg, 4.7 mmol) in THF (15 mL) was added sodium hydroxide (474 mg, 11.8 mmol) and tetrabutylammonium hydrogen sulfate (80.5 mg, 0.24 mmol). The reaction mixture was stirred at r.t. for 1 h and then treated with ethyl iodide (887 mg, 5.7 mmol) dropwise. The resulting mixture was stirred at r.t. overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc in heptane) to afford 6-Bromo-1-ethyl-4-methyl-1H-indazole (476 mg, 42%). 1H NMR (600 MHz, CDCl3) δ 1.51 (t, 3H), 2.57 (s, 3H), 4.38 (q, 2H), 7.04-7.06 (m, 1H), 7.43 (s, 1H), 7.97 (d, 1H). MS (AP+)(M+H) 239.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:35][C:34](=[O:44])[CH:33]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[NH:35][C:34](=[O:44])[CH:33]=4)=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc(N)cc1
Product: CCC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 84 mg (purity 90%, 0.28 mmol, 1.1 eq.) of tert-butyl 5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 17 mg (purity 70%, 8% of theory)
Reaction SMILES: [OH-].[Na+].FC(F)(F)C([N:7]1[C@@H:16]2[C@@H:11]([C:12]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[CH:17][C:13]=3[CH2:14][CH2:15]2)[CH2:10][CH2:9][CH2:8]1)=O>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:12]3[C@@H:11]4[C@H:16]([CH2:15][CH2:14][C:13]=3[CH:17]=2)[NH:7][CH2:8][CH2:9][CH2:10]4)=[CH:27][CH:26]=1
Reactant: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
1 M aqueous NaOH solution (10 mL) is added to a solution of cis-2,2,2-trifluoro-1-[8-(4-methoxy-phenoxy)-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl]-ethanone (0.95 g) in tetrahydrofuran (10 mL) at room temperature. The resulting solution is stirred at 35° C. overnight and then cooled to room temperature. The solution is extracted with ethyl acetate, the combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 95:5→70:30) to give the title compound as a colorless resin-like solid. Yield: 0.64 g (88% of theory); LC (method 1): tR=2.75 min; Mass spectrum (ESI+): m/z=310 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.CO.C(Cl)Cl>CCCCCC>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[S:22][CH3:21])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: CSc1ccccc1B(O)O
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: CSc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 72 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-(methylthio)benzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (508) (I; Ar=2-(methylsulfanyl)phenyl) in a 72% yield, mp (MeOH/CH2Cl2)/hexane) 208–216° C. 1H NMR [(CD3)2SO] δ 11.76 (br s, 1H), 10.95 (br s, 1H), 9.25 (br s, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.43 (td, J=7.3, 2.2 Hz, 1H), 7.38 (br d, J=7.5 Hz, 1H), 7.27 (dd, J=7.8, 2.2 Hz, 1H), 7.24 (td, J=7.3, 1.3 Hz, 1H), 7.07 (dd, J=8.7, 2.5 Hz, 1H), 2.32 (s, 3H). Found: C, 66.55; H, 3.88; N, 7.38. C21H14N2O3S.1/4H2O requires C, 66.57; H, 3.86; N, 7.39.
Reaction SMILES: [ClH:1].[OH:2][C:3]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[BH4-].[Na+].[OH-].[Na+].Cl>CO>[ClH:1].[OH:2][C:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)[OH:14])[CH2:6][CH2:5]1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid, methyl ester hydrochloride (550mg, 1.00 mmol) in methanol (5 mL) and add sodium borohydride (62.8mg) in three batches. Stir for 1 hour, add 50% aqueous sodium hydroxide (800mg).and heat to reflux with stirring. After 3 hours, cool to −10° C., add approximately 1.5 mL of 6N HCl over 10 minutes, filter the solid and wash with ice water (12 mL) such that the final filtrate is pH=5. Dry the resulting solid in vacuo (50-60° C., 10−1 mm) overnight to give the title compound (515mg, 94%); mp 165-180° C.