Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:3]=1.CCN(CC)CC.[NH2:30][OH:31].Cl>CCO>[OH:31][N:30]=[C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]=[C:2]2[I:1])[NH2:12]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C#N)ccc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(N)=NO)ccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
To a suspension of 3-iodo-1-tosyl-1H-indole-5-carbonitrile (1 g, 2.37 mmol) in EtOH (10 mL) was added Et3N (1.65 mL, 11.87 mmol) followed by NH2OH.HCl (410 mg, 5.93 mmol) and the reaction was stirred for 48 h at RT. The solvent was removed in vacuo and the residue was treated with H2O (10 mL) and extracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was further triturated with n-pentane to give N′-hydroxy-3-iodo-1-tosyl-1H-indole-5-carboximidamide (950 mg, 88.7%) as an off brown solid. MS (ESI, pos. ion) m/z: 455.8; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.8 Hz, 1H), 7.84-7.73 (m, 4H), 7.68 (d, J=8.4 Hz, 1H), 7.63-7.61 (m, 1H), 7.31-7.24 (m, 1H), 4.92 (brs, 2H), 3.14-3.09 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:37]([O:36][C@H:17]1[CH2:18][C@H:19]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[CH:6]([CH:2]=[O:1])[CH3:7])[CH2:16]1)(=[O:39])[CH3:38]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 100 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregna-5,7-diene, followed by addition of 1 ml of water and 10 mg of p-toluenesulfonic acid. The mixture was stirred in an atmosphere of argon gas at 50° C. for 3 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 45 mg of 3β-acetoxy-1α-benzoyloxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[O:45][CH:46]=[CH:47][N:48]=3)=[CH:40][CH:39]=2)O1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:4]3[N:5]([C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=4)[N:10]=3)[N:6]=[CH:7][C:2]=2[C:38]2[CH:43]=[CH:42][C:41]([C:44]3[O:45][CH:46]=[CH:47][N:48]=3)=[CH:40][CH:39]=2)=[CH:24][CH:25]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12
Reactant: CC1(C)OB(c2ccc(-c3ncco3)cc2)OC1(C)C
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(-c4ncco4)cc3)cnn12

Procedure:
7-Chloro-8-(4-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, prepared as described in Example 277 and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole were reacted using procedures analogous to those described in Example 276 to give the title compound, 8-(4-chlorophenyl)-7-(4-(oxazol-2-yl)phenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. HPLC: 99% at 8.42 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 549 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 5.32 (s, 2H), 7.23-7.32 (m, 2H), 7.40-7.59 (m, 4H), 7.62-7.78 (m, 4H), 7.90-8.05 (m, 2H), 8.24-8.27 (m, 1H), 8.81 (s, 1H).
Reaction SMILES: Cl.N1C=CC=CC=1.C(O[CH:11](OCC)[N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[N:17][N+:18]([O-:20])=[O:19])C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCN(C)C1=O>O>[C:31]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[N:17][N+:18]([O-:20])=[O:19])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN1CCN(C)C1=O
Product: O=[N+]([O-])N=C1NCCN1C=Nc1ccccc1-c1ccccc1
Reaction time: 0.33 h
Yield: 48.1 %

Procedure:
0.25 g of pyridine hydrochloride was added to a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 3.64 g of o-aminobiphenyl and 3 ml of 1,3-dimethyl-2-imidazolidinone at 100° C., followed by agitation at the same temperature for 20 minutes. The reaction mixture was poured into water, extracted with ethyl ether, washed with water, dried and concentrated, followed by addition of ether to the resultant oily residue. The resulting crystals were collected by filtration and dried to give 3.2 g of 1-(2-phenylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.C(Cl)Cl.CO.[C:43]1(=O)[CH2:47][CH2:46][CH2:45][CH2:44]1>CC(O)=O>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:43]6[CH2:47][CH2:46][CH2:45][CH2:44]6)[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C1CCCC1
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(C3CCCC3)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 3 h
Yield: 4.5 %

Procedure:
To a solution of N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide (100 mg, 0.19 mmol) in AcOH:DCM:MeOH (2.5 mL, 1:2:2) was added cyclopentanone (100 μL, 1.09 mmol), borane-pyridine complex (100 μL, 0.8 mmol), and left to stir for 3 h. The solvent was then removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (5.0 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.35 (m, 2 H) 1.38-1.78 (m, 11 H) 1.96 (br. s., 2 H) 2.67 (br. s., 1 H) 2.87 (t, J=7.33 Hz, 2 H) 3.49 (t, J=7.33 Hz, 2 H) 3.91 (s, 3 H) 4.08 (t, J=13.77 Hz, 2 H) 4.33-4.44 (m, 1 H) 4.78-4.88 (m, 1 H) 7.19 (d, J=6.57 Hz, 1 H) 8.05 (s, 1 H) 8.25 (d, J=13.39 Hz, 1 H) 8.30 (s, 1 H) 8.41 (dd, J=6.82, 3.03 Hz, 1 H). [M+H] calc'd for C29H36F3N7O3, 588; found 588.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:7]1=[O:26].C([SiH](CC)CC)C.C(OCC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:11][C:9]1([CH3:12])[CH2:10][NH:6][C:7](=[O:26])[CH:8]1[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:24])([F:23])[F:25])[CH:15]=1
Reactant: COc1ccc(CN2CC(C)(C)C(Oc3ccc(C#N)c(C(F)(F)F)c3)C2=O)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC1(C)CNC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A solution of 4-[1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-2-oxo-pyrrolidin-3-yloxy]-2-trifluoromethyl-benzonitrile (25 g; 56 mmol) in trifluoroacetic acid (250 mL)and triethylsilane (20 g; 169 mmol; 3 eq) was brought to gentle reflux overnight. The reaction was cooled to ambient temperature. The reaction mixture was concentrated in vacuo to give an oily residue. The crude product was dissolved in dichloromethane and was washed with saturated aqueous sodium bicarbonate and with brine solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dark purple oily residue. The product was purified by flash silica column chromatography. Elution with a gradient (100% hexanes to 3:2 v/v ethyl acetate-hexanes over 1 hour, 12 minutes; pump speed: 1 mL/min) afforded an off-white powder. Trituration with diethyl ether over a steam bath afforded 14.6 g of a white powder; 1H-NMR (400 MHz; CDCl3) δ 7.75 (dd, 1H, J=8.6, 0.4 Hz), 7.46 (d, 1H, J=2.5 Hz), 7.37 (dd, 1H, J=8.6, 2.5 Hz), 6.46 (s, 1H), 4.53 (s, 1H), 3.21 (s, 1H), 3.20 (s, 1H), 1.27 (s, 3H), 1.25 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ −62.66 (s, 3F); MS (APCl+) 299.1 (M+1, 100); (APCl−) 186.0 (100)
Reaction SMILES: Cl.[C:2]([C:4]([O:31][Si](C)(C)C)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:15]2)=[O:13])=[CH:7][CH:6]=1)#[N:3]>C1COCC1>[C:2]([C:4]([OH:31])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:15]2)=[O:13])=[CH:9][CH:10]=1)#[N:3]
Reactant: C[Si](C)(C)OC(C#N)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N#CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
) HCl 3N (0.010 mol) was added to a solution of (±)-N-[4-[cyano[(trimethylsilyl)oxy] phenylmethyl]phenyl]4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.010 mol) in THF (50 ml). The reaction mixture was stirred for 15 minutes at 65° C. The reaction mixture was washed with water and extracted with EtOAc. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 4.2 g of (±)-N-[4-(cyanohydroxyphenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 495).
Reaction SMILES: BrC(C1C=CC2OC3C(=CC=CC=3)CC=2C=1)CC.C([O-])(=O)C.[K+].C(O[CH2:28][CH:29]([C:31]1[CH:44]=[CH:43][C:42]2[O:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][C:33]=2[CH:32]=1)[CH3:30])(=O)C>CN(C=O)C>[CH:32]1[C:33]2[CH2:34][C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:41][C:42]=2[CH:43]=[CH:44][C:31]=1[C:29]([CH3:30])=[CH2:28]
Reactant: CC(=O)OCC(C)c1ccc2c(c1)Cc1ccccc1O2
Agent: CC(=O)[O-]
Agent: CCC(Br)c1ccc2c(c1)Cc1ccccc1O2
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
3 g. of 1-bromo-(2-xanthenyl)-propane is dissolved in 20 ml. of DMF, mixed with 3 g. of anhydrous potassium acetate, and stirred for 3 hours at 60°. The mixture is worked up as usual, thus obtaining 2-(2-xanthenyl)-propyl acetate, m.p. 62°-64°. Additionally, a small amount of 2-(2-xanthenyl)-propene is produced.
Reaction SMILES: C[Mg]Cl.OC[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[C:14]([OH:17])(=O)[CH3:15].C1C[O:21]CC1>ClCCl>[OH:21][C:8]([C:13]1[CH:12]=[CH:11][CH:10]=[CH:15][C:14]=1[OH:17])([CH3:9])[CH3:6]
Reactant: CC(=O)O
Reactant: O=C(CO)c1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Solvent: ClCCl
Product: CC(C)(O)c1ccccc1O
Yield: 45 %

Procedure:
To a stirred solution of methyl magnesium chloride (134 ml, 3M in THF) kept under nitrogen, at 0° C. was added a solution of 2-hydroxy acetophenone (50 g, 367 mmol) in anhydrous THF (100 ml). The reaction mixture was stirred. After completion of the reaction, the reaction mixture was treated with 4M acetic acid (500 ml) followed by usual workup in dichloromethane and FC to give hydroxy phenol 31 (25 g, 45%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].CCN(CC)CC.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22].Cl>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[S:21]([O:12][C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])(=[O:22])=[O:20]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])cc(Br)c1OS(=O)(=O)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 2-bromo-6-methyl-4-nitrophenol (110.0 g, 0.474 mol) in DCM (950 mL) at −70° C. was added Et3N (62.3 g, 0.616 mol) and Tf2O (147.1 g, 0.521 mol). The resulting solution was stirred at −70° C. for 20 min. TLC showed the reaction was complete. Aqueous HCl (0.5 M, 1 L) was added to quench the reaction. The DCM layers were separated, dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by silica gel column (Petroleum Ether→Petroleum Ether:EtOAc (20:1)) to afford desired 2-Bromo-6-methyl-4-nitrophenyl trifluoromethanesulfonate (146.7 g, 85%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.41 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:16][C@@H:17]2[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C@H:19]([C:35]([N:37]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH:46]=[CH:45][N:44]=[CH:43]4)[CH2:38]3)=[O:36])[CH2:18]2)=CC=1.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>[SH:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:23])[C@H:19]([C:35]([N:37]2[CH2:41][CH2:40][C@H:39]([N:42]3[CH:46]=[CH:45][N:44]=[CH:43]3)[CH2:38]2)=[O:36])[CH2:18]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4ccnc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](n2ccnc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
585 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-(imidazol-1-yl)pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in a mixture of 5 ml of anisole and 15 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 1 hour and then at 35° C. for a further 30 minutes. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the resulting residue was washed four times with diethyl ether, to give a colorless powder. This powder was suspended in ethyl acetate, and the suspension was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated and washed with an aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.9 g of the title compound, as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][OH:17])[CH:7]=[C:6]2[C:18]1[N:26](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][OH:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCO)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCCO)c2cc1OC
Yield: 61.7 %

Procedure:
3-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propanol is prepared by following the procedure described in example 88a, but using 0.24 g of 3-[5,6-dimethoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propanol and a solution of 9.3 ml of methanolic potassium hydroxide (0.1 g/ml; 1.78M). After purification by flash-pack chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents), 0.103 g of 3-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propanol is obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[CH:40]([NH:43][CH:44]([CH3:46])[CH3:45])([CH3:42])[CH3:41]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([N:43]([CH:44]([CH3:46])[CH3:45])[CH:40]([CH3:42])[CH3:41])=[O:20])=[CH:15][N:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)O)s1
Reactant: CC(C)NC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)N(C(C)C)C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a solution of (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetic acid (Example 3) (0.09 g, 0.25 mmol) in CH2Cl2 (5.0 mL) and DMF (0.5 mL) were added EDCI (0.05 g, 0.27 mmol), DMAP (0.02 g, 0.12 mmol), triethylamine (0.1 mL, 0.75 mmol) and diisopropylamine (0.04 mL, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with 1 M HCl (2×15 mL) and the organic layer was collected. The organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification using preperative HPLC afforded the desired product (0.01 g) in 9% yield.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:17]2[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14][C:13]=2[C:12]([N+:22]([O-:24])=[O:23])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCOCC>C1C=CC=CC=1>[N:28]1([C:9]2[C:17]3[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14][C:13]=3[C:12]([N+:22]([O-:24])=[O:23])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: C1CCNCC1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1N1CCCCC1

Procedure:
Triethylamine (1.0 gram; 0.00968 mole) was added to 3.0 grams of 4-chloro-5,7-dinitro-2-trifluoromethylbenzimidazole (0.00968 mole) in 200 milliliters of benzene. There was then added dropwise 0.8 gram of piperidine (0.00968 mole) in 10 milliliters of benzene. The resulting reaction mixture was refluxed overnight, cooled, an amount of ether added, and the mixture filtered. The filtrate was evaporated, yielding the desired 4-piperidino-5,7-dinitro-2-trifluoromethylbenzimidazole product as an orange solid. It was recrystallized from benzene as a light brown solid, m.p., 199°-206° C. NMR analysis confirmed the identity but suggested the presence of a small amount of triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][NH:11][C:10]2=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24].O>CN(C)C=O>[CH2:23]([O:25][C:26]([N:12]1[C:13](=[O:14])[N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:10](=[O:15])[NH:11]1)=[O:27])[CH3:24]
Reactant: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)n1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 2.5 g of 4-(3',5'-dichlorophenyl) urazole and 1 g of triethylamine in 10 ml of N,N-dimethylformamide was added dropwise 1.1 g of ethylchloroformate with agitation. The reaction and agitation were continued at room temperature for one hour. The reaction mass was mixed with water to precipitate crystals which were filtered and recrystallized from acetone-ethanol to obtain 2.3 g of 1-ethoxycarbonyl-4-(3',5'-dichlorophenyl) urazole, which constituted a yield of 72%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:22]([OH:24])=O)=[N:10][C:11]([C:18]([F:21])([F:20])[F:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.Cl.[NH2:26][CH2:27][C:28]([CH3:34])([OH:33])[C:29]([F:32])([F:31])[F:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN1C(=O)CCC1>[F:30][C:29]([F:32])([F:31])[C:28]([OH:33])([CH3:34])[CH2:27][NH:26][C:22]([C:9]1[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])=[CH:13][C:12]([C:14]([F:15])([F:17])[F:16])=[C:11]([C:18]([F:21])([F:19])[F:20])[N:10]=1)=[O:24]
Reactant: CC(O)(CN)C(F)(F)F
Reactant: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)NCC(C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate M) (1.16 g, 3.29 mmol) in NMP (32 ml) was added 3-Amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (commercially available) (591 mg, 3.29 mmol) followed by HATU (1.25 g, 3.29 mmol) and NEt3 (918 ul, 6.59 mmol) and the reaction mixture was left to stir at RT. After 1 h a further 0.2 equiv. NEt3 was added. After 15 min a further 0.4 equiv. NEt3 and 0.2 equiv. amine were added. After 30 min a further 0.1 equiv HATU was added. After 30 min most of the starting material had been consumed. The reaction mixture was added to EtOAc (50 ml), washed with 0.1M NaOH and the aqueous layer was back extracted with EtOAc (2×50 ml). The combined organic extracts were washed with water (2×150 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the crude product as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[N:16].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)nc2c1Cl
Product: CC(C)(C)OC(=O)Cn1c(C(F)(F)F)nc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 200A from 4-chloro-2-(trifluoromethyl)-1H-benzimidazole-5-carbonitrile and 1,1-dimethylethyl bromoacetate: MS (APCI) m/z 360 (M+1).