Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].C1COCC1.Cl[Si](C)(C)C.[C:42]1([CH2:48][C:49](Cl)=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:49](=[O:50])[CH2:48][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(O[C@H](C(=O)O)[C@]2(c3ccccc3)c3ccccc3CCN2C(=O)Cc2ccccc2)c1
Yield: 46.8 %

Procedure:
To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (60 mg, 0.143 mmol, Example 1) in THF (5 ml) Hünig's base (122 μl, 0.715 mmol) followed by chlorotrimethylsilane (22 μl, 0.172 mmol) is added at 5° C. The mixture is stirred at 55° C. for 3 h before phenylacetylchloride (29 μl, 0.215 mmol) is added. Stirring is continued at rt for 2 h before water (approx. 200 μl) is added. The mixture is diluted with DCM, washed twice with 2 N aq. HCl. The organic phase is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC on Rp-C18 silica gel to give (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-2-phenylacetyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (36 mg) as a white powder. LC-MS1: tR=0.98 min, [M+1]+=538.13.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)COCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-(2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butan-1-ol (step 3) (50 mg, 0.139 mmol) in toluene (1 ml) was added KOH (40% aq, 1 ml, 0.139 mmol) and tetrabutylammonium hydrogen sulfate (47.2 mg, 0.139 mmol) followed after 5 min at RT, by tertiary butyl bromoacetate (90 uL). The reaction mixture was stirred at RT for 24 h. The mixture was diluted with ether and the phases were separated. The aqueous portion was extracted with ether (×2), the combined organics were dried (sodium sulphate), filtered and the solvent removed in vacuo. The residue was dissolved in THF (1 ml) followed by the addition of KOH (40% aq, 1 ml, 0.139 mmol), tetrabutylammonium hydrogen sulfate (47.2 mg, 0.139 mmol) and tertiary butyl bromoacetate (88 uL). The reaction mixture was stirred at RT for 6 h. The mixture was diluted with ether and stirred at RT for 12 h. The phases were separated, the aqueous extracted with ether (×2), the combined organics were dried (sodium sulphate), filtered and the solvent removed in vacuo. The crude material was purified on silica eluting with 0-100% EtOAc/DCM to afford the title compound:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][CH2:14][CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1>CO>[NH:18]1[CH:17]=[C:16]([CH2:15][CH2:14][NH:13][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[N:20]=[CH:19]1
Reactant: NCCc1c[nH]cn1
Reactant: CSc1nc(Cl)n2nccc2n1
Solvent: CO
Product: CSc1nc(NCCc2c[nH]cn2)n2nccc2n1

Procedure:
A solution of 30 mg 4-chloro-2-methylthiopyrazolo(1,5-a)-1,3,5-triazine and 33 mg free histamine in 3 ml of methanol is stirred at room temperature overnight. After evaporation of solvent, the residue is dissolved in ethylacetate, washed with water, and dried over MgSO4. After removal of solvent, the residue is subject to silica gel preparative thin layer chromatography using CHCl3 /methanol=9:1 as a developing solvent. Appropriate fractions are isolated, extracted with CHCl3 /CH3OH (3:1), and solvent removed in vacuo to dryness. 20 mg of a white solid are recovered. TLC (silica gel CHCl3 /CH3OH=3:1) Rf=0.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:30]1([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][NH2:41])[CH2:34][CH2:33][CH2:32][CH2:31]1>C(N(CC)CC)C.O>[CH:30]1([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][NH:41][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([O:12][CH3:13])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(OC)c(S(C)(=O)=O)cc1C(=O)O
Reactant: NCC1CCCN1C1CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc(OC)c(S(C)(=O)=O)cc1C(=O)NCC1CCCN1C1CCCC1
Reaction time: 0.67 h

Procedure:
91 g of 2,4-dimethoxy-5-methylsulphonyl benzoic acid, 400 ml of acetone, 130 ml of water and 48.6 ml of triethylamine are placed in a liter flask fitted with an agitator, a thermometer and a dropping funnel. 47.6 g of isobutyl chloroformate is dripped into the solution obtained, at about 10° C. It is agitated for 40 minutes, then 58.8 g of 1-cyclopentyl-2-aminomethyl-pyrrolidine is poured in drop by drop at about 0° C. A precipitate appears after 30 minutes of agitation at room temperature. It is allowed to react then the precipitate is filtered off, washed with water and dried. 74 g of a crude version of the product is obtained, melting at 198° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.[S:16](N)(N)(=[O:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]1(=[O:18])=[O:17]
Reactant: Nc1ccccc1Nc1ccccc1F
Reactant: NS(N)(=O)=O
Product: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Yield: 39.4 %

Procedure:
In an analogous manner to general procedure I, step 3, N-(2-fluorophenyl)benzene-1,2-diamine (1.0 g, 5.0 mmol) was treated with sulfamide (0.58 g, 6.0 mmol) to provide 0.52 g (40%) of 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C12H9FN2O2S+Na+, 287.02609; found (ESI, [M+Na]+), 287.0263; HPLC purity 100.0% at 210-370 nm, 8.4 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:26][CH2:25]1)=[O:23].O.Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]1)=[O:23]
Reactant: CCOC(=O)CN1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Potassium hydroxide (320 mg) was added to a solution of ethyl 4-{3-[5-chloro-2-(4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}piperazine-1-acetate (Example 109, 350 mg, 0.72 mmol) in methanol and the mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 7.0 with hydrochloric acid (2M). The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was crystallised from ethyl acetate:methanol (99:1) to give the title compound as a pale solid (300 mg, 90%). 1H NMR (250 MHz, CD3OD) δ2.20-2.26 (2H, m), 2.92-2.97 (2H, m), 3.10-3.25 (4H, m), 3.55-3.60 (2H, m), 3.90-4.01 (4H, m), 7.10 (1H, dd, J 8.8, 2.0 Hz), 7.38 (1H, d, J 8.8 Hz), and 7.45-7.60 (5H, m). m/z (ES+) 460, 462 (M+1).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>C(Cl)Cl.C(OCC)(=O)C>[CH:26]1([NH:29][C:2]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C(F)(F)F)ccc1NC1CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
1 g of 2-fluoro-5-trifluoromethyl-benzoic acid (4.81 mmol) was dissolved in DCM (10 ml) and 1.03 ml of oxalylchloride (12.01 mmol) and a drop of DMF were added at RT. The mixture was stirred for 1 h before all volatile materials were removed in vacuo. The remaining residue was again dissolved in DCM (10 ml) and 1.4 ml of ethanol was added. After 1 h the reaction mixture was diluted with DCM and then washed with 10% aqueous KHCO3 solution, water and brine, dried (MgSO4), filtered and concentrated. The remaining material was dissolved in DMSO (6 ml), 5.57 ml of cyclopropylamine (79.4 mmol) were added and the mixture was heated to 110° C. over night in a sealed tube. The reaction mixture was then cooled to RT, diluted with ethyl acetate, washed with diluted HCl, 10% aqueous KHCO3 solution, water and brine, dried (MgSO4), filtered and concentrated. Then THF (20 ml), methanol (10 ml) and 8 ml of a 1N LiOH solution were added and the resulting solution was stirred over night at RT. The organic solvents were then removed in vacuo and the solution was acidified with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The remaining solid was triturated with a small amount of chloroform. Filtration gave 391 mg (33%) of the title compound as light brown crystals. 1HNMR (DMSO-d6, 300 MHz): δ 0.53 (m, 2H), 0.85 (m, 2H), 2.56 (m, 1H), 7.24 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.9 and 2.1 Hz, 1H), 8.02 (s, 1H), 8.30 (br s, 1H), 13.21 (br s, 1H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH2:22](OC1C=CC(C(OC)=O)=CC=1)[CH2:23]CCCCCCCC.C([O-])([O-])=O.[K+].[K+].COC(=O)C1C=CC(O)=CC=1.BrCCCCCCCCC=C>>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:22][CH3:23]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: C=CCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: C=CCCCCCCCCBr
Agent: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Product: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
Methyl 4-(dec-9-enyloxy)benzoate (3). Synthesized as described above for compound 1. Quantities: K2CO3 (18.2 g, 0.13 mol), methyl-4-hydroxy-benzoate (6.30 g, 41.4 mmol), 10-bromo-1-decene (8.6 mL, 42.8 mmol). Yield 12.0 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 1.23-1.51 (10 H, m, CH2), 1.77 (2 H, m, O—CH2—CH2), 2.03 (2 H, m, CH2═CH—CH2), 3.85 (3 H, s, OCH3), 3.95 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.79 (1 H, m, CH2═CH), 6.87 (2 H, d, 3J=9.0 Hz, Ar—H), 7.98 (2 H, d, 3J=9.0 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.0, 28.9, 29.0, 29.1, 29.3, 29.4, 51.7, 68.1, 114.0, 114.2, 122.3, 131.5, 139.0, 162.9, 166.7.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:7])[C:5]#[CH:6].Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl>O1CCCC1>[CH3:3][CH:4]([O:7][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]#[CH:6]
Reactant: C#CC(C)O
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)OCC(=O)OC
Reaction time: 0.58 h

Procedure:
A mechanically stirred suspension of sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol) in tetrahydrofuran (160 mL) at 0° C. under nitrogen was treated with a solution of (±)-3-butyn-2-ol (21 g, 0.30 mol) in tetrahydrofuran (35 mL) over 30 minutes, stirred for 35 minutes, treated with a solution of methyl bromoacetate in tetrahydrofuran (50 mL) over 10 minutes, stirred for 30 minutes at 0° C., stirred at ambient temperature for 16 hours and treated with 2M HCl (150 mL). The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×, 100 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, concentrated and distilled under vacuum to provide the title compound (20 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:46][CH2:47][CH3:48])[C:44]=5[CH3:45])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:46][CH2:47][CH3:48])[C:44]=5[CH3:45])=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncn(CCC)c4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncn(CCC)c4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1-propylimidazol-4-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (220 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (119 mg) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. Dimethylsulfide (0.1 ml) was added to the mixture and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure: and the obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=10:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1-propylimidazol-4-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (132 mg) (Compound 441) as yellow amorphous.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=2[N:14]=1.[ClH:20]>C(#N)C.[Cu](Cl)Cl>[Cl:20][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=2[N:14]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1cccc2sc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution containing copper chloride (II) (1.96 g, 14.61 mmol) and tri(ethylene glycol) dimethyl ether (6 mL) in acetonitrile (100 mL) was added isoamyl nitrite (2.14 g, 18.27 mmol), and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 2-amino-4-methylbenzothiazole (2.0 g, 12.18 mmol) in tri(ethylene glycol) dimethyl ether (10 mL). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (400 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water, brine, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage Flash 40M) using 5% ethyl acetate in hexane to afford 2-chloro-4-methyl-1,3-benzothiazole (1.6 g, 71%). 1H NMR (400 MHz, CD2Cl2) δ 2.70 (s, 3H), 7.32 (m, 2H), 7.64 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C[N:25]1C(=O)CCC1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[NH2:25])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(=O)OC(C)(C)C
Reactant: CN1CCCC1=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(N)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a solution of 3-tert-butoxycarbonylamino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (4.3 g, 12.8 mmol) in NMP (64 mL) was added K-OtBu (1.6 g, 14.1 mmol). After 10 min a solution of 0-4-nitrobenzoylhydroxylamine (3.0 g, 16.6 mmol) in NMP (16 mL) was added dropwise and the reaction was allowed to stir for 16 h. The reaction was quenched with LiCl solution (5% in water, 50 mL) and diluted with EtOAc (50 mL). The crude product was washed 3×50 mL with 5% LiCl solution, dried over Na2SO4, and purified by silica gel chromatography 0-30% EtOAc/hexanes to give 3-(N-tert-butoxycarbonyl-hydrazino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.6 g, 7.4 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:5]=[CH:4][N:3]=1.[NH2:21][NH2:22]>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:21][NH2:22])[C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: Clc1ccc(-c2ncnc(Cl)c2-c2ccccc2)cc1
Solvent: C1CCOC1
Product: NNc1ncnc(-c2ccc(Cl)cc2)c1-c1ccccc1
Temperature: 60 °C

Procedure:
To a stirred solution of 4-chloro-6-(4-chlorophenyl)-5-phenylpyrimidine (301 mg, 1.0 mmol) in THF (5 mL) at room temperature under argon was added H2NNH2 (160 mg, 5.0 mmol). The reaction mixture was heated at 60° C. under argon for 2 h. Analysis by HPLC/MS indicated that the reaction was complete. The solvent was evaporated and the residue was coevaporated with toluene (2×5 mL) and THF (5 mL), then dried under vacuum. The crude title compound was used directly in the next step. HPLC/MS: retention time=1.89 min, [M+H]30 =297.
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[CH:17]=[C:16]([CH:18]=[C:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)[CH:15]=[CH:14][C:13]=1[OH:34].C([O-])(O)=O.[Na+].[OH-].[Na+].Cl>O.CO>[CH:29]1[C:24]2[CH2:23][CH2:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[C:19](=[CH:18][C:16]3[CH:15]=[CH:14][C:13]4[O:34][C:2](=[O:3])[NH:11][C:12]=4[CH:17]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1O
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1[nH]c2cc(C=C3c4ccccc4CCc4ccccc43)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.1 %

Procedure:
Add phenyl chloroformate (24 μL, 0.195 mmol) to a suspension of 2-amino-4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (61 mg, 0.195 mmol) (see Example 63) and NaHCO3 (16 mg, 0.195 mmol) in water (5 mL) and methanol (10 mL). Stir for 30 min at room temperature and add aqueous NaOH (1.00N, 195□L). Stir overnight and add aqueous HCl (1.00N, 195□L). Extract with CH2Cl2, dry organics (MgSO4), and concentrate to a brown oil containing the title compound. Purify on silica gel (10 g) eluting with 10% TO 35% ethyl acetate/hexanes, and then triturate with 50% CH2Cl2/hexanes to afford 8 mg (13%) of a white solid. MS (ES) 357 (M+NH4), 338 (M−H); HPLC shows 94% purity.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH:11]=1)[C:7]#[N:8].[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:35])[CH2:33]Br)=[C:27]([Cl:36])[CH:26]=1)(=[O:24])=[O:23]>CN(C=O)C>[NH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:35])[CH2:33][O:19][C:17]2[CH:18]=[C:13]([O:12][C:10]3[CH:9]=[C:6]([C:7]#[N:8])[CH:5]=[C:4]([Cl:3])[CH:11]=3)[CH:14]=[C:15]([Cl:20])[CH:16]=2)=[C:27]([Cl:36])[CH:26]=1)(=[O:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)cc(Cl)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Nc3ccc(S(N)(=O)=O)cc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid sodium hydride (18 mg, 0.458 mmol) was added in portions to a DMF solution of 128 mg (0.458 mmol) of 3-chloro-5-(3-chloro-5-hydroxyphenoxy)benzonitrile (B-4). This was stirred for 30 minutes at room temperature and then 75 mg (0.229 mmol) of solid N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (A-3) was added. The reaction was then stirred at 50° C. for 14 hours until an LC/MS analysis indicated that the reaction was complete. The product was purified by a reverse phase hplc column on a Gilson unit. Clean fractions were combined and concentrated in vacuo to give the desired product 2-1 as an amorphous solid. HRMS: measured 525.9788; theoretical 525.9793. 1H NMR (DMSO-d6): 4.91 (s, 2H), 6.80 (m, 1H), 6.89 (m, 1H), 7.03 (m, 1H), 7.48 (s, 2H), 7.54 (m, 1H), 7.60 (m, 1H), 7.77 (d, 1H), 7.85 (s, 1H), 7.91 (s, 1H), 8.02 (d, 1H), 9.87 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[O:7]1[CH2:11][CH2:10]OC1=O>CCN(CC)CC>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:10][CH2:11][OH:7]
Reactant: O=C1OCCO1
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Product: OCCOCC(F)(F)F
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2,2,2-trifluoroethanol (15 g), 1,3-dioxolan-2-one (19.8 g) and Et3N (15 g) were mixed together, and then the mixture was heated to 100° C. and stirred for 24 h. Then the reaction mixture was distilled to obtain intermediate BR (12.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH2:31][N:32]4C(=O)C5=CC=CC=C5C4=O)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O.NN.O.CCOC(C)=O>CCO>[NH2:32][CH2:31][CH2:30][N:28]1[CH:29]=[C:9]2[C:10]([N:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:27]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Yield: 66.7 %

Procedure:
To a solution of 4,6-bis(4-fluorophenyl)-2-(2-phthalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.09 g, 0.2 mmol, obtained in example 89) in EtOH (2 mL), hydrazine monohydrate (0.02 g, 0.3 mmol) was added and the mixture was heated to reflux for 3 h. A mixture of water and EtOAc was added. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using CHCl3-MeOH mixtures of increasing polarity as eluent, to afford 57 mg of the title compound (yield: 83%).