Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:19])[C:15](O)([CH3:17])[CH3:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5].CCN(S(F)(F)[F:26])CC.O>C(Cl)(Cl)Cl>[F:26][C:15]([CH3:17])([CH3:16])[CH:14]([CH3:19])[O:13][C:11]1[CH:12]=[C:7]([O:6][CH2:1][C:2]#[C:3][CH2:4][CH3:5])[N:8]=[CH:9][N:10]=1
Reactant: CCC#CCOc1cc(OC(C)C(C)(C)O)ncn1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC#CCOc1cc(OC(C)C(C)(C)F)ncn1
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
First, 0.31 g of 4-(2-pentynyloxy)-6-(2-hydroxy-1,2-dimethylpropyloxy)pyrimidine was dissolved in 3 ml of chloroform, to which 0.5 ml of a solution containing 0.24 g of DAST in chloroform was added dropwise at 0° C., followed by stirring for 10 minutes. The reaction mixture was then poured into water, which was extracted three times with chloroform. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of 4-(2-fluoro-1,2-dimethylpropyloxy)-6-(2-pentynyloxy)pyrimidine (the present compound (17)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CC([N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=C(B(O)O)C=2)C1)C.O=C1CCN(C(OC(C)(C)C)=O)CC1.S(=O)(=O)(O)N.[ClH:48]>C(O)(=O)C>[ClH:48].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:19]1[CH2:24][CH2:25][NH:17][CH2:21][CH:20]=1
Reactant: CC(C)N1Cc2ccc(B(O)O)cc2C1
Reactant: NC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: NS(=O)(=O)O
Solvent: CC(=O)O
Product: NC(=O)c1cc(Br)cc2c(C3=CCNCC3)c[nH]c12
Temperature: 72 °C
Reaction time: 0.5 h

Procedure:
5-bromo-1H-indole-7-carboxamide (which may be prepared according to Intermediate 7, WO2005067923) (1 wt), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1.20 wt, 1.5 eq) and sulfamic acid (0.5 eq, 0.2031 wt) were all charged sequentially to an empty reactor. Acetic acid (5 vols) was added and the mixture was heated to 70-74° C. Held thus with stirring under nitrogen for 15-25 hrs until the level of 5-bromo-1H-indole-7-carboxamide by HPLC is <5% a/a uncorrected. A mixture of hydrochloric acid (36%, 0.52 vol, 1.5 eq) and acetic acid (0.5 vol) was prepared. This mixture was then added drop-wise to the batch over ca 30 mins, maintaining an internal temp of 65-74° C. The batch was stirred for a further 30 mins at 65-74° C. before warming to 93-97° C. Stirred within this temp range under nitrogen for 15-25 hrs, until the 2:1 dimer impurity (rrt 1.15 on 8 min reverse phase LC method) is <10% a/a uncorrected. Batch then cooled back to 15-25° C. and aged within this temp range for at least 60 mins. Product then collected by vacuum filtration and washed with IMS (2×2 vol). Dried to constant weight at 40° C. in vacuo.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:30][CH:31]=[C:26]4[C:25]([C:38]#[N:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:44])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:30][CH:31]=[C:26]4[C:25]([C:38]([NH2:39])=[O:44])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CN(C)CCNc1ccc2c(C#N)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Solvent: O
Product: CN(C)CCNc1ccc2c(C(N)=O)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-(dimethylamino)ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (19 mg, 34.3 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1.47 mg, 3.43 μmol, Eq: 0.1) were combined with Ethanol (271 μl) and Water (271 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo, then diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(2-dimethylamino-ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (14.2 mg, 71%, [M+H]+ 572).
Reaction SMILES: [F:1][CH:2]([F:22])[C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21].C([O-])(=O)C.[K+]>CC(C)=O.S(=O)(=O)(O)O.C(OCC)(=O)C.O.O.O.[Cr]>[F:1][CH:2]([F:22])[C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21]
Reactant: O=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C(F)F)[C@@H](O)CC[C@@H]34)[C@H]2CC1
Agent: [Cr]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C(F)F)C(=O)CC[C@@H]34)[C@H]2CC1

Procedure:
310 mg of crude 18,18-difluoro-17β-hydroxy-oestr-4-en-3-one (18,18-difluoro-19-nor-testosterone) are dissolved in 40 ml of acetone and oxidised for 5 minutes at 0° C with about 1.5 equivalents of a 8 N solution of chromium-VI oxide in dilute sulphuric acid (Jones reagent). Saturated potassium acetate solution is added to the reaction mixture and the resulting mixture is diluted with ethyl acetate and the organic layer is washed with a saturated sodium chloride solution until neutral, dried and evaporated in an aspirator vacuum. The resulting residue is dissolved in a mixture of hexane/ethyl acetate (2:1) and filtered through 20 times the amount by weight of silica gel. The evaporated fractions give 18,18-difluoro-oestr-4-ene-3,17-dione, which after recrystallisation from methylene chloride/hexane melts at 186°-189° C. IR spectrum: 1745, 1670 and 1620 cm-1.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.1773 mmol). Methane sulfonyl chloride 342 (13.5 mg, 0.1182 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 343. 1H NMR (400 MHz, DMSO) δ: 11.94 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H), 8.03 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d, 1H), 4.31 (m, 1H), 3.66 (m, 2H), 2.95 (s, 3H), 2.16 (m, 2H), 2.01 (m, 2H) and MS ES+502.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:26]=[CH:25]2>>[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=4)[CH2:11][CH2:10]3)=[O:8])[CH2:3][CH2:2]1)(=[O:34])=[O:33])[CH:26]=[CH:25]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1)N1CCN(c2ccncc2)CC1
Yield: 20 %

Procedure:
Using an analogous procedure to that disclosed in Example 2, 1-(4-piperidinylcarbonyl)-4-(4-pyridyl)piperazine was reacted with 6-bromonaphth-2-ylsulphonyl chloride to give 1-[1-(6-bromonaphth-2-ylsulphonyl)piperidin-4-ylcarbonyl]-4-(4-pyridyl)piperazine in 20% yield, m.p. 229-230° C.;
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:16]=3[CH2:17][OH:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1.C[N+]1([O-])CCOCC1.ClCCl.C(#N)C>ClCCl.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:16]=3[CH:17]=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1
Reactant: CCCCc1nn(CC(F)(F)F)c(CO)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CCCCc1nn(CC(F)(F)F)c(C=O)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
A mixture of the product of Example 5 (0.55 g), 4Å molecular sieves (powdered) (2.5 g), N-methylmorpholine-N-oxide (0.65 g) in a mixture of dry dichloromethane (10 ml) and dry acetonitrile (10 ml) was treated with tetrapropylammonium perruthenate (40 mg) at 0°. The mixture was stirred at 0° to ambient temperature for 1.5 h and filtered through "hyflo", and the solvent was evaporated. The residue was purified by flash column chromatography eluting with System F (400:400:10:10) to give a residue which was dissolved in a mixture of dichloromethane:ethyl acetate (2:1;25 ml) and washed with water (50 ml). (The pH of the aqueous solution was adjusted to 4 with aqueous sodium carbonate (2N)). The organic phase was, dried, filtered and evaporated to give the title compound as an off-white solid (0.31 g).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[F:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([F:32])[C:25]([F:33])=[CH:24][C:23]=1[C:34]1[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=1.CI.Cl>C1COCC1>[F:21][C:22]1[C:27]([C:28]([F:31])([F:29])[F:30])=[C:26]([F:32])[C:25]([F:33])=[C:24]([CH3:1])[C:23]=1[C:34]1[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=1
Reactant: CC(C)NC(C)C
Reactant: CC1(C)COC(c2cc(F)c(F)c(C(F)(F)F)c2F)=N1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)c(F)c(C(F)(F)F)c(F)c1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
A solution of 1.12 g (11.0 mmol) of diisopropylamine in 5 ml of THF was cooled to 0° C. under nitrogen, treated with 4.0 ml of 2.5M n-butyllithium, and stirred for 10 minutes. This lithium diisopropylamide solution was added dropwise to a solution of 2.36 g (8 mmol) of 2-[2,4,5-trifluoro-3-(trifluoromethyl)-phenyl]-4,4-dimethyl-2-oxazoline in 5 ml of THF at -78° C. The solution was stirred at -78° C. for one hour, then quenched with 2.24 g (16 mmol) of methyl iodide. The mixture was allowed to warm slowly to room temperature, stirred for one hour, and poured into 10 ml of 1N HCl. This solution was extracted with ether, and the extract was washed with water, dried over magnesium sulfate, and concentrated to give 2.28 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=3)[S:16][C:10]=2[C:9]=1[OH:28])=[O:7].[OH-].[Li+]>CO>[CH2:24]([O:23][C:20]1[N:19]=[CH:18][C:17]([C:15]2[S:16][C:10]3[C:9]([OH:28])=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:29])=[O:2])=[O:7])[N:13]=[CH:12][C:11]=3[N:14]=2)=[CH:22][CH:21]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOc1ccc(-c2nc3cnc(C(=O)NCC(=O)OC)c(O)c3s2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
To a solution of {[2-(6-butoxy-pyridin-3-yl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid methyl ester (10.6 mg, 0.026 mmol) in methanol (1 mL) was added lithium hydroxide aqueous solution (1N, 0.51 mL) at ambient temperature. The reaction mixture was stirred at 50° C. for 1.5 h. After the solvent was evaporated off, 10 mL of water was added. The aqueous solution was adjusted to pH 2-3 by addition of 1N hydrochloric acid, and extracted twice with ethyl acetate. The combined organic layers were dried, filtered, and concentrated to afford 6.5 mg of a white solid. MS: (+) m/z 403.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[CH3:18].[OH-].[Na+]>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2′-hydroxy-2-methylbiphenyl-4-carboxylate (3 g; 12.38 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with sodium hydroxide (7.43 mL; 5 M; 37.15 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid. It was taken up in water (250 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated and extracted with EtOAc giving the title compound as an orange oil. It was purified by flash chromatomatography eluting with EtOAc:cHex (1:1) affording the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.88 (br s, 1H), 9.49 (s, 1H), 7.81-7.75 (m, 2H), 7.24-7.18 (m, 2H), 7.05-7.02 (m, 1H), 6.94-6.84 (m, 2H), 2.16 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 3.26 min (Purity: 95.1%).
Reaction SMILES: [OH-].[Na+].C([C:5]1[N:6]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:21]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]2)[CH3:22])=[O:20])[S:8][C:9]=1[C:10]([OH:12])=[O:11])C.Cl>C(O)C>[C:35]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[NH:33][C:32]([O:31][CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][N:21]([CH3:22])[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:7]2[S:8][C:9]([C:10]([OH:12])=[O:11])=[CH:5][N:6]=2)[CH2:30][CH2:29]1)=[O:46]
Reactant: CCc1nc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 10 N aqueous sodium hydroxide solution (27 μL) was added to a solution of the compound obtained in Example 104a in ethanol (3.0 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was ice cooled, then a 6 N aqueous hydrochloric acid solution (453 μL, 1) was added, and then the solvent was evaporated under reduced pressure. Methanol (2 mL) and toluene (10 mL) were added to the residue, and the solvent was evaporated under reduced pressure again to give crude 2-({6-[(2-{4-[(biphenyl-2-ylcarbamoyl)oxy]piperidin-1-yl}ethyl)(methyl)amino]-6-oxohexyl}amino)-1,3-thiazole-5-carboxylic acid (357 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]([OH:29])=O)=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:22])([F:24])[F:23])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:29]
Reactant: NCCCCO
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCCCO)c(F)cc21
Yield: 75.4 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (4-hydroxy-butyl)-amide (44 mg) was prepared by General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (50 mg), 4-amino-1-butanol (12 mg), HBTU (53 mg), and DIEA (31 uL). LC/MS: m/z 497.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.89-7.59 (m, 2H), 7.58-7.40 (m, 1H), 7.36 (d, 1H), 4.44 (s, 1H), 3.62 (s, 3H), 3.49-3.39 (m, 2H), 3.32-3.20 (m, 2H), 1.67-1.36 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].N1C=CC=CC=1>[O-2].[Cu+2].ClCCl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(Oc2ccc(C=O)cc2)cc1
Yield: 56.2 %

Procedure:
To a mixture of Example 17A (1.50 g, 9.86 mmol), 4-bromobenzaldehyde (2.20 g, 11.9 mmol.), (K2CO3 (2.85 g, 20.6 mmol) and pyridine (50 mL) at 80° C. was added Cu(II) oxide (1.95 g, 24.5 mmol). After the addition, the mixture was refluxed vigorously for 20 hours. After cooling, dichloromethane was added and the mixture was filtered through Celite. The filtrate was concentrated to dryness. The residue was dissolved in ether, which was washed with 10% HCl (2×), 1N NaOH (2×), brine (1×), dried over MgSO4, and concentrated to dryness. The residue was purified on silica gel eluting with a hexane and ethyl acetate gradient to give the desired product as a white solid (1.42 g, 56%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[CH2:4][CH2:5][OH:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:6][CH2:5][CH2:4][CH:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1([CH3:11])[CH3:1])(=[O:14])[CH3:13]
Reactant: CC1(C)C=CC=CC1CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCC1C=CC=CC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 2,2-dimethylphenethyl alcohol (118.0 g, 0.786 mol) in pyridine (700 mL). Add, by dropwise addition, acetic anhydride (222 mL, 240.7 g, 2.358 mol) and stir overnight at room temperature. Evaporate the solvent in vacuo and purify by distillation to give the title compound as a clear colorless oil; bp 75° C. @0.4 mmHg.
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Br:15]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[Br:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(=O)N2CCCc3cc(Br)cc1c32
Reaction time: 5 h

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (10 g) and N-bromosuccinimide (10 g) in DMF (60 ml) was stirred at 7020 C. for 5 hours. After cooling, to the mixture was added ethyl acetate (500 ml) and washed with water and saturated aqueous sodium chloride solution successively, and then dried over anhydrous sodium sulfate. Evaporation of ethyl acetate afforded the title compound. The compound was recrystallized from ethanol to give 14 g (98.4%) as dark red needles.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[NH2:17]>>[CH3:24][O:23][C:19]1[CH:18]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:15]=[C:14]([O:13][CH3:12])[C:20]=1[O:21][CH3:22]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2ccccc2CC(=O)O)cc(OC)c1OC

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,4,5-trimethoxyaniline to yield 2-[(3,4,5-trimethoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of ethyl 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanate (3.58 g), 2N aqueous sodium hydroxide solution (10.0 mL), tetrahydrofuran (10 mL) and methanol (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (3.34 g, yield 99%) as pale-yellow crystals. melting point 234-235° C.