Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+](CC)(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.[C:36](Cl)([Cl:39])([Cl:38])[Cl:37]>C(Cl)(Cl)Cl>[Cl:37][C:36]([CH:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[OH:33])([Cl:39])[Cl:38]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ccc(C=O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Yield: 94.5 %

Procedure:
A 10 g quantity of tetraethyl ammonium salt of p-toluenesulfonic acid was dissolved in 60 ml of dimethylformamide containing 0.1 mole of chloroform. The solution was placed in a cathode chamber and in an anode chamber. Further 13.6 g (0.1 mole) of p-methoxybenzaldehyde and 0.01 mole of carbon tetrachloride was introduced into the cathode chamber. A glass filter was used as a diaphragm. Electrolysis was conducted at a constant current of 0.1 A. After current (2 F/mole) was passed, the reaction liquid was withdrawn from the cathode chamber. The carbon tetrachloride and chloroform were distilled off and the residue was extracted with methylene chloride. The methylene chloride was distilled off from the extract and the residue was distilled in a vacuum, giving trichloromethyl-4-methoxyphenyl carbinol. Yield 94.5%, b.p. 122°-124° C./1 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:18][CH:17]=2)[CH:15]=1.[CH3:30][N:31]1[CH2:36][CH:35]=[C:34](B(O)O)[CH2:33][CH2:32]1.[F-].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][N:31]1[CH2:32][CH:33]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)[CH2:35][CH2:36]1
Reactant: CN1CC=C(B(O)O)CC1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC=C(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Temperature: 150 °C

Procedure:
A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), 1-Methyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (Boron Molecular, 221 mg; 0.99 mmol; 3.0 eq.), PdCl2(PPh3)2 (23 mg; 0.03 mmol; 0.10 eq.), cesium fluoride (151 mg; 0.99 mmol; 3.0 eq.) in dioxane (3 mL) and water (1.5 mL) was degassed with nitrogen flow and heat in MW at 150° C. for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three time with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as a yellow powder. 1H NMR (300 MHz, DMSO) δ 13.36 (brs, 1H), 9.39 (s, 1H), 8.31 (s, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.78-7.47 (m, 4H), 6.32-6.11 (m, 1H), 3.84-3.49 (m, 6H), 3.46-3.25 (m, 2H), 3.11-2.98 (m, 2H), 2.71-2.58 (m, 4H), 2.30 (s, 3H). HPLC (Condition A): Rt 2.22 min (purity 94.5%). MS (ESI+): 470.3, MS (ESI−): 468.3.
Reaction SMILES: C(OC(=O)C)(=O)C.[NH2:8][C:9]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].C([O-])(=O)C.[K+].[N+:26]([O-])(OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:20][C:16]1[CH:17]=[C:18]2[C:9](=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[NH:8][N:26]=[CH:19]2
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: CC(C)CCO[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Br)cc2cn[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
Acetic anhydride (4.5 g, 4.1 mL, 44 mmol) was added dropwise to the homogenous solution of methyl 2-amino-5-bromo-3-methylbenzoate (4.72 g, 19 mmol) in chloroform (55 mL) over a period of 20 min at room temperature and allowed to stir for 1 h. Potassium acetate (5.7 g, 58 mmol) and isoamyl nitrate (6.6 g, 7.6 mL, 57 mmol) were added at once to the reaction mixture under nitrogen. The clear reaction mixture turned to dark upon heating at 90° C. The reaction mixture was cooled to room temperature after overnight reflux, concentrated, diluted with water and stirred. The beige solid formed was collected by filtration and dried to obtain methyl 5-bromo-1H-indazole-7-carboxylate (2.1 g, 42%). 1H NMR (DMSO-d6): δ 13.44 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 3.95 (s, 3H).LCMS: rt 6.86 min (A), purity 99%, MS (m/e) 255 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[S:50][CH:49]=[N:48][CH:47]=1>>[CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:46]3[S:50][CH:49]=[N:48][CH:47]=3)=[CH:17][CH:18]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: Brc1cncs1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2cncs2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 5-bromothiazole. MS (ESI): mass calcd. for C32H28N4O3S, 548.19; m/z found, 549.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.83 (d, J=9.1, 1H), 8.32-8.28 (m, 2H), 8.18 (d, J=8.8, 1H), 8.01-7.93 (m, 2H), 7.79 (t, J=7.5, 1H), 7.68-7.59 (m, 3H), 7.49 (s, 1H), 7.34 (d, J=7.8, 3H), 5.84 (s, 2H), 5.69 (s, 2H), 3.54 (s, 2H), 1.31 (s, 6H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:34][C:33](=O)[CH2:32]1>>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([NH:28][CH:33]4[CH2:34][O:31][CH2:32]4)[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C1COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(N)C3)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(NC4COC4)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 45-1 in Scheme 20 by using 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine and oxetan-3-one (prepared in analogy to Example 25) and oxetan-3-one. MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CD3OD) δ ppm 7.99-7.97 (m, J=2.2 Hz, 1 H), 7.83-7.80 (t, J=2.9 Hz, 2 H), 7.64-7.60 (m, J=4.1 Hz, 1 H), 7.47-7.43 (m, J=4.5 Hz, 2 H), 7.29-7.26 (m, J=2.5 Hz, 1 H), 6.12 (s, 1 H), 5.15 (s, 2 H), 4.85 (m, 2 H), 4.56 (m, 4 H), 4.14 (m, 1 H), 3.73 (m, 2 H), 3.60 (m, 3 H), 3.42 (m, 2 H), 2.40 (s, 3 H), 2.21 (m, 1 H), 1.87 (m, 1 H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]=O)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:52]6[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]6)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)c1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide (40.1 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial, with fitted magnetic stir bar, containing piperazine (0.18 mmol), and acetic acid (3.6 mg, 0.6 mmol). The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and purification was completed via Gilson HPLC (with 0.1% TFA in the solvents). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 29.8 mg (65.3%) of the title compound. LC-MS m/z 760 (M+H)+, 1.224 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[C:9]([O:15][C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[C:1]([O:5][C:6](=[O:27])[C:7]1[C:12]([CH2:13][Br:48])=[CH:11][CH:10]=[C:9]([O:15][C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(CO)c(C(=O)OC(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(CBr)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of 650 mg of 3-(tert-butoxycarbonylaminoacetoxy)-6-hydroxymethylbenzoic acid tert-butyl ester and 580 mg of triphenylphosphine was added 848 mg of carbon tetrabromide, and the mixture was stirred for 2 h at room temperature. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Column chromatography on silica gel gave 322 mg of 3-(tert-butoxycarbonylaminoacetoxy)-6-(bromomethyl)benzoic acid tert-butyl ester as a colourless oil; 1H-NMR(CDCl3) δ 1.34(9H,s), 1.51(9H,s), 4.08(2H,br.d,J=5.6 Hz), 4.80(2H,s), 4.95(1H,br.s), 7.12(1H,dd,J=8.6,2.6 Hz), 7.34(1H,d,J=8.6 Hz), 7.51(1H,d,J=2.6 Hz)
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Br:6][C:7]1[C:8]([Cl:17])=[N:9][CH:10]=[C:11]([S:13](Cl)(=[O:15])=[O:14])[CH:12]=1>C(Cl)Cl.N1C=CC=CC=1>[N:2]1([S:13]([C:11]2[CH:12]=[C:7]([Br:6])[C:8]([Cl:17])=[N:9][CH:10]=2)(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(c1cnc(Cl)c(Br)c1)N1CCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 37.3 %

Procedure:
Azetidine hydrochloride (0.32 g, 3.44 mmol) was added to a solution of 3-bromo-2-chloropyridine-5-sulfonyl chloride (1 g, 3.44 mmol) in DCM (4 mL) and pyridine (10 mL) and stirred at RT for 22 hours. The solvent was removed in vacuo and ethyl acetate (30 mL) added. The organic phase was washed with 1M hydrochloric acid (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound (0.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NOCCO)c1cc(C=NOCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCCO)c(F)c2F)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyimino)-methyl]-benzamide (334 mg, 0.620 mmol) prepared in Example 1 was dissolved in anhydrous tetrahydrofuran (10 mL). (PPh3)2PdCl2 (20,867-1, Sigma-Aldrich Inc.) (21 mg, 0.031 mmol), copper iodide (11 mg, 0.0062 mmol), N,N-diisopropylethylamine (130 μL, 0.774 mmol), and trimethylsilylacetylene (1 mL) were then added thereto at room temperature. The mixture was stirred at 50° C. for two hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C(#N)C.[Cl:11][CH2:12][C:13](Cl)=[O:14]>ClCCCl>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)=[O:14]
Reactant: Nc1cncnc1
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(CCl)Nc1cncnc1
Temperature: 80 °C

Procedure:
5-Aminopyrimidine (450 mg) was suspended in DCE (2 mL) and acetonitrile (2 mL) in a microwave vial. Chloroacetyl chloride (0.377 mL) was added with stirring. The vial was sealed and the reaction mixture was heated in the microwave at 80° C. for 5 minutes. The solid was filtered off, washed with acetonitrile (2×5 mL), DCE (2×5 mL) and pentane (2 ×30 mL) and then partioned between saturated sodium bicarbonate and DCE (50 mL/50 mL) ensuring the aqueous layer was still basic. The organic layer was separated and the aqueous layer was extracted with DCE (2×75 mL). The combined organic layer was dried over magnesium sulfate and evaporated to give the sub-titled compound (200 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10]([CH:12]=O)=O>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Cc1ccc(N)c(N)c1
Solvent: CO
Product: Cc1ccc2nccnc2c1
Reaction time: 16 h
Yield: 25 %

Procedure:
A solution of 4-methyl-1,2-phenylenediamine (5.0 g, 41 mmol) in methanol (250 mL) was treated with a solution of 40% aqueous glyoxal and stirred for 16 h. The solvent was evaporated and the residue was distilled under vacuum (2 mm Hg, 85-88° C.) to leave a colorless oil (1.5 g, 25%). LC/MS Method A, r.t.=1.02 mins., purity=99.5%.
Reaction SMILES: C([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1)(=O)C.Cl.[CH3:27]O>>[NH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:27])=[O:23])[CH:17]=1
Reactant: CO
Reactant: CC(=O)Nc1c(C(=O)c2cccc(C(=O)O)c2)[nH]c2cc(Cl)ccc12
Agent: Cl
Product: COC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Temperature: 60 °C

Procedure:
A mixture of 3-acetylamino-6-chloro-2-(3-carboxybenzoyl)indole (Example 132, 0.9 g, 2.5 mmol) and 10% HCl—MeOH (30 ml) was heated at 60° C. for 8 h. The mixture was cooled and concentrated, and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated and washed with brine (50 ml), and dried (MgSO4) and solvent removed by evaporation. The residual solid was purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to afford 0.5 g of a title compound as a yellow solid. m.p.: 187-189° C. (ethyl acetate/hexane) 1H-NMR (DMSO-d6) δ: 9.14 (1H, br s), 8.47 (1H, dd, J=1.8, 1.1 Hz), 8.20 (1H, ddd, J=7.7, 1.8, 1.1 Hz), 8.03 (1H, ddd, J=7.7, 1.8, 1.1 Hz), 7.69-7.58 (2H, m), 7.28 (1H, d, J=1.8 Hz), 6.97 (1H, dd, J=1.4, 8.4 Hz), 6.04 (2H, br s), 3.95 (3H, s)
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:1][C:2]1[C:7]([NH:8][C:18](=[O:19])[CH2:17][Cl:16])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(C)n1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)CCl)c(C)n1
Reaction time: 1 h

Procedure:
A solution of 2,6-dimethyl-3-aminopyridine (24.9 grams) in ether (200 ml), and pyridine (21 grams) are charged into a glass reaction vessel equipped with mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to a temperature below about 10° C and chloroacetyl chloride (11.3 grams) is slowly added over a period of about 15 minutes. Stirring and cooling is continued for an additional period of about 1 hour to ensure the completion of the reaction. The resulting precipitate is then recovered by filtration, is washed with aqueous potassium carbonate and with water, and is dried to yield the desired product N-(2,6-dimethyl-3-pyridyl)-α-chloroacetamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.CN1CCOCC1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21](=[O:22])[O:12][CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(OCCc1c[nH]c2ccccc12)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
To a solution of 2-(1H-indol-3-yl)-ethanol (1600 mg, 9.92 mmol), in N-methyl morpholine (2000 m g, 19.84 mmol), was added p-nitrophenyl chloroformate (4000 mg, 19.84 mmol), and the mixture was stirred for 24 hours at room temperature. Water was added and the mixture extracted with dichloromethane. Evaporation of the solvent gave a residue which was purified by silica gel column chromatography using a mixture of DCM/Hx (3:1) as eluent to produce 1034 mg (32%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH2:10]([CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)[CH3:11]>>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:12]2[CH2:10][CH3:11])[C:7]=1[F:8]
Reactant: CCC1CCCCCN1
Reactant: Fc1c(Cl)ncnc1Cl
Product: CCC1CCCCCN1c1ncnc(Cl)c1F
Reaction time: 1 h
Yield: 97.2 %

Procedure:
0.4 g of 4,6-dichloro-5-fluoropyrimidine and 0.61 g of 2-ethylhexahydro-1H-azepine were mixed and left for 1 hour at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.6 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-2-ethylhexahydro-1H-azepine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:21][NH2:22]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=1)[C:3]([NH:21][NH2:22])=[O:2])([O-:12])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Reactant: NN
Product: NNC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Yield: 74 %

Procedure:
A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (4.0 g, 14.7 mmol) and hydrazine (5 mL, 80%) was refluxed for 4 h to yield 5-nitro-2-phenoxy-benzoic acid hydrazide (2.97 g, 74%). The title compound was prepared from 5-nitro-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=6.6 Hz, 1H), 7.81 (m, 1H), 7.75 (t, J=6.6 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.35 (m, 2H), 7.27 (d, =J=7.2 Hz, 1H), 7.03 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 70.8 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (85 mg, 0.23 mmol) and 3-(trifluoromethyl)benzyl bromide (200 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with water (3×20 mL), 50% aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-100% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (108 mg, 71%) as a white solid. APCI(+)-MS (M+H) 463.
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([NH:27][NH2:28])(=O)=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:2]1([C:1]2[C:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[NH:27][N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccccc2)Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 18 h

Procedure:
A mixture of 2-benzylidene-indan-1-one (3.99 g), p-toluenesulphonyl hydrazine (4.0 g), p-toluenesulphonic acid hydrate (0.7 g) and ethanol (60 ml) was boiled under reflux for 1.5 hours and then left to stand for 18 hours at ambient temperature. The mixture was boiled under reflux for a further 74 hours and then left to stand at ambient temperature for 74 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and 2M sodium hydroxide solution (50 ml). The organic layer was separated, dried over magnesium sulfate and filtered. The magnesium sulfate was washed with ethyl acetate and filtered. The ethyl acetate filtrate was evaporated to dryness to give a solid which was recrystallized from ethanol to give 3-phenyl-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 234-236° C.