Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([F:22])=[CH:20][N:19]=2)[CH2:25][CH2:26]1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(F)cn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(F)cn2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
3-chloro-2′,5′-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (0.0509 g, 0.150 mmol) was dissolved in anhydrous DMSO (3.0 ml) and charged to a microwave vial. This was treated with trans-cyclohexane-1,4-diamine (0.171 g, 1.498 mmol). The reaction mixture was then heated at 100° C. for 18 hr. More trans-cyclohexane-1,4-diamine (0.171 g, 1.498 mmol) was added and the reaction mixture was stirred at 120° C. for 18 hr. The reaction mixture was allowed to cool to ambient temperature. The material was purified by preparative reverse-phase HPLC to give 0.2410 g (30%) of N2′-(trans-4-aminocyclohexyl)-3-chloro-5′-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as the TFA salt. LCMS (m/z): 434.2 (MH+), retention time=0.55 min.
Reaction SMILES: [BrH:1].[CH2:2]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>COCCOC>[Br:1][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1
Reactant: Br
Reactant: C=CCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: O=C(O)c1ccc(NCCCCCCCCCCCBr)cc1

Procedure:
Anhydrous hydrogen bromide is passed rapidly into a solution of 5 g. of 4-(10-undecenylamino)benzoic acid and 1 g. of dibenzoyl peroxide in 300 ml. of 1,2-dimethoxyethane for 1 hour. Partial evaporation of the solvent affords a crystalline solid which is separated by filtration and recrystallized from etherpetroleum ether to yield the product as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:17]2[C:16]3[N:15]=[C:14]([S:18][CH3:19])[N:13]=[CH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:7]([C:20]([OH:22])=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:1]([N:5]1[C:17]2[C:16]3[N:15]=[C:14]([S:18][CH3:19])[N:13]=[CH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:7]([C:20]([NH:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)=[O:22])=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ncc2ccc3c(C(=O)O)nn(C(C)(C)C)c3c2n1
Reactant: NOC1CCCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2ccc3c(C(=O)NOC4CCCCO4)nn(C(C)(C)C)c3c2n1
Yield: 49.4 %

Procedure:
1-tert-butyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid 40 mg (0.112 mmol) was reacted in dry DMF (2 ml) with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine 25 mg (0.21 mmol), TBTU 70 mg (0.21 mmol) and DIPEA 0.110 ml (1.19 mmol) at room temperature for 3 hours. The reaction was worked up with water, saturated NaHCO3 and extracted with ethyl acetate. The organic phase, dried on Na2SO4, filtered and evaporated, was purified on silica with DCM/EtOAc 7/3 to give 23 mg (50%) of 1-tert-butyl-8-(methylsulfanyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide. LC/MS (m/z): 416.1 [M+H]+, HPLC (254 nm) method 3 Rt 6.94 min.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([NH:43][CH:44]1[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([CH3:52])[C:46]([CH3:54])([CH3:53])[CH2:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][NH:43][CH:44]2[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([CH3:52])[C:46]([CH3:54])([CH3:53])[CH2:45]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN1C(C)(C)CC(NC(=O)CCl)CC1(C)C
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCNC2CC(C)(C)N(C)C(C)(C)C2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 32.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)acetamide (23 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (9.6 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21](SC)=[N:22][CH:23]=[C:18]3[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[CH2:44]([NH2:46])C>C(Cl)Cl>[CH3:44][NH:46][C:21]1[N:20]=[C:19]2[N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:32])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH2:10]3)[N:16]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]2=[CH:23][N:22]=1
Reactant: CSc1ncc2c(-c3ccccc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Reactant: CCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNc1ncc2c(-c3ccccc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of tert-Butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.14 g, 0.3 mmol) in methylene chloride (5 mL) was added meta-chloroperoxybenzoic acid (0.20 g, 0.9 mmol) at room temperature. After stirring at room temperature for 2 h, the light purple solution was quenched with a 1.0 N aqueous solution of NaOH. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4), and concentrated. The residue was dissolved in THF (1 mL), followed by the addition of ethylamine (1.5 mL, 2.0 M in THF, 3 mmol). The resulting solution was heated at 60° C. for 2 h, cooled to room temperature, and concentrated. The crude mixture was purified by Isco to provide tert-butyl 4-((6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.085 g, 81%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:10])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH3:22])[C:20]#[N:21]>CN(C)C=O>[CH3:10][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH3:22])[C:20]#[N:21]
Reactant: Cc1ccccc1O
Reactant: CN(C#N)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1OCc1ccccc1N(C)C#N
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 124.8 %

Procedure:
1 g (0.024 mol) of a 60% sodium hydride suspension is suspended in 10 ml of dimethylformamide and admixed with a solution of 2.2 g (0.02 mol) of ortho-cresol in 10 ml of dimethylformamide, and the mixture is stirred at 20° C. for 40 minutes. A solution of 11.3 g (0.02 mol) of 40% pure N-(2-bromomethylphenyl)-N-methyl-cyanamide in 10 ml of dimethylformamide is added, and the mixture is stirred at 20° C. for 18 hours. The mixture is stirred into 200 ml of ice/sodium chloride solution and extracted with ether. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The residue is chromatographed over silica gel using cyclohexane/ethyl acetate (3:1). 6.3 g of N-[2-(2-methylphenoxymethyl)-phenyl]-N-methyl-cyanamide of a content of 40% (HPLC) are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:44])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH3:31])[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:44])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH3:31])[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)C(CC1CCC(O)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 41 (1.23 g, 1.86 mmol) in tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) (1.9 mL, 1.9 mmol). The reaction was stirred at room temperature under argon for 4 hours, then the reaction was poured into water (20 mL). Brine (80 mL) was added, and the reaction extracted with dichloromethane (3×80 mL). The organics were dried (MgSO4) and the solvent removed in vacuo. Column chromatography (dichloromethane:methanol 9:1) gave the product as a white foam, 1.54 mmol, 83%.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[NH4+]>Cl>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Yield: 88.3 %

Procedure:
4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acid(which was obtained in Example 150) (12.5 g, 47.5 mmol) was treated with concentrated hydrochloric acid (500 mL) at room temperature. After 15 hours ˜28% ammonium hydroxide was added dropwise and the precipitate was collected by filtration, and dried over phosphorus pentoxide to give the title compound as a white solid (9.2 g, 88%); 1H NMR (300 MHz, CDCl3) δ 2.46 (t, J=6.1 Hz, 4H), 3.74 (t, J=6.1 Hz, 4H), 7.02 (d, J=9.0 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H); MS (ES) m/z: 219.8 (MH+); HRMS Calcd. for C12H14NO3 (MH+): 220.0974. Found: 220.0947.
Reaction SMILES: COC[O:4][C:5]1[C:6]([O:12][CH2:13][CH2:14][OH:15])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][O:12][C:6]1[CH:7]=[C:8]([CH3:11])[N:9]=[CH:10][C:5]=1[OH:4]
Reactant: COCOc1cnc(C)cc1OCCO
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(OCCO)c(O)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 168.1 %

Procedure:
2-(5-(Methoxymethoxy)-2-methylpyridin-4-yloxy)ethanol (900 mg, 4.22 mmol) was dissolved in ethyl acetate (10 mL), added 4N hydrochloric acid-ethyl acetate solution (10 mL), and the mixture was stirred at room temperature for 5 hours. After the reaction has terminated, under ice-cold conditions, a 4N aqueous solution of sodium hydroxide was used to adjust the reaction solution to pH=8. The reaction solution was concentrated in vacuo. The obtained residue was washed with chloroform/methanol, dried, and as a crude product, 4-(2-hydroxyethoxy)-6-methylpyridin-3-ol (1.2 g) was obtained as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: NCCCO
Product: CCOC(=O)c1ccnc(CNCCCO)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 3-aminopropan-1-ol. Purification by column chromatography (0-5% MeOH in DCM) gave the title compound. 1H NMR (300 MHz, CDCl3), δ ppm: 8.72 (d, 1H), 7.98 (s, 1H), 7.75 (d, 1H), 4.45 (q, 2H), 3.95 (s, 2H), 3.70 (t, 2H), 2.80 (t, 2H), 1.75 (m, 2H), 1.40 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C1C=CC2N(O)N=NC=2C=1.[CH:20]12[NH:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][O:22][CH2:21]2.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH:24]12[N:27]([C:7]([C:4]3[S:5][CH:6]=[C:2]([Br:1])[N:3]=3)=[O:9])[CH:20]([CH2:26][CH2:25]1)[CH2:21][O:22][CH2:23]2
Reactant: C1CC2COCC1N2
Reactant: O=C(O)c1nc(Br)cs1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(c1nc(Br)cs1)N1C2CCC1COC2
Temperature: 0 °C
Reaction time: 15 h
Yield: 17.15 %

Procedure:
To a solution of 4-bromothiazole-2-carboxylic acid (prepared according to the procedure given in WO 2008/57336, 1.4 g, 6.73 mmol) in DMF (15 ml) was added HOBT (1.13 g, 7.40 mmol) at room temperature, followed by the addition of 3-oxa-8-azabicyclo[3.2.1]octane (prepared according to the procedure given in WO 2010/120854, 0.76 g, 6.69 mmol). Reaction mixture was cooled to 0° C. and to this were added EDC (1.93 g, 10.10 mmol) and triethylamine (3.40 g, 4.69 ml, 33.60 mmol). Reaction mixture was stirred at room temperature for 15 hr. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was taken in ethyl acetate (150 ml) and washed with saturated sodium bicarbonate solution (1×40 ml), brine (1×20 ml). The organic layers separated were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 2.5% methanol in DCM as an eluent to obtain the title compound (0.35 g. 17.15%). MS: m/z 304 (M+1).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C.[CH3:31][CH2:32]N(CC)CC.C(Cl)(=O)C=C>C(Cl)Cl.Cl.O1CCOCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][N:8]1[C:6](=[O:5])[CH:31]=[CH2:32])[CH3:30]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CN1C(=O)OC(C)(C)C
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CC(=O)N1Cc2ccccc2C1c1cc(Cl)ccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.16 g, 5.0 mmol, 1.0 eq.) in DCM (100 mL), 4M HCl in dioxane (25 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. To a solution of the residue and NEt3 (3.48 mL, 25 mmol, 5.0 eq.) in DCM (100 mL), acryloyl chloride (0.45 mL, 5.5 mmol, 1.1 eq.) was added. The resulting solution was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane+20% AcOEt to Heptane+70% AcOEt) to give the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=O)=O.Br.Br.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[NH:35][CH:36]2[CH2:37][CH2:38][N:39]([CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[CH2:40][CH2:41]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1ccc(CCOS(C)(=O)=O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of 2.3 parts of 2-(4-methoxyphenyl)ethyl methanesulfonate, 4.9 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide is stirred overnight at 70° C. The reaction mixture is poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 2.2 parts (48%) of 1-(4-fluorophenylmethyl)-N-{1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine; mp. 172.9° C.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[CH2:13][C:14]([CH3:16])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][C:14](=[CH2:13])[CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: C=C(C)CCl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1ccccc1C(=O)OC
Yield: 37 %

Procedure:
A mixture of 152 g of methyl salicylate, 99 g of 3-chloro-2-methylpropene, 151.8 g of potassium carbonate, and 500 ml of acetone was heated at reflux overnight. After cooling, the mixture was extracted with diethyl ether and ethyl acetate. The organic extracts were combined, washed twice with a 10% sodium chloride solution and water, dried over sodium sulfate, and concentrated in vacuo. The resulting liquid was vacuumed distilled. The fraction collected at 120°-121° C. and 1.5 torr provided 76.2 g of the desired subtitle intermediate. NMR, MS.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:10]([F:15])[F:14])[CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)Oc1cncc(Br)c1

Procedure:
A mixture of 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland, 1.394 mmol), sodium chlorodifluoroacetate (Aldrich, Buchs, Switzerland, 1.672 mmol) and potassium carbonate (2.79 mmol) in acetonitrile (10 ml) was refluxed for 4 h 45 min. The reaction was cooled and diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated to give the title compound as a brown oil. (HPLC: tR 2.91 min (Method A); M+H=224, 226 MS-ES).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:33]=[CH:32][N:31](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:33]=[CH:32][NH:31][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]5)=[CH:22][CH:23]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(N5CCC(O)CC5)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 60 °C
Yield: 12.6 %

Procedure:
To a solution of 1-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperidin-4-ol (11 mg, 0.018 mmol) in methanol (MeOH) (1 mL), aq. 1N KOH (0.50 mL, 0.50 mmol) was added. The mixture was heated at 60° C. for 24 h. It was then concentrated in vacuo. The residue was acidified with acetic acid (HOAc) (1.0 mL) before being purified by HPLC to give the title compound (1 mg). MS 441.1 (M+H) (Compound 7-1).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH3:55][NH2:56]>>[CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@@H](CC(C)(C)C(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CN
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@@H](CC(C)(C)C(=O)NC)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2S,4R,5R)-4-[4((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound as a yellow oil. Rf=0.28 (EtOAc/heptane 8:1); Rt=5.29 (gradient I).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH3:7])[N:6]=1.[F:8][C:9]([F:23])([F:22])[C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH:13]=O>C1(C)C=CC=CC=1>[CH3:7][N:5]1[N:4]=[N:3][C:2]([N:1]=[CH:13][C:12]2[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=[C:10]([C:9]([F:8])([F:22])[F:23])[CH:11]=2)=[N:6]1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cn1nnc(N)n1
Solvent: Cc1ccccc1
Product: Cn1nnc(N=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
A mixture 5-amino-2-methyltetrazole (5.00 g, 50 mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (19.5 g, 81 mmol) in toluene (100 mL) is stirred and refluxed for 3 hours. The resulting mixture is concentrated to give crude 2-methyl-N-[3,5-bis(trifluoromethyl)phenylmethylene]-2H-tetrazole-5-amine.
Reaction SMILES: [C:1](O)(=O)[CH2:2]C.[CH3:6][CH2:7][C@@:8]1([OH:31])[C:13](=[O:14])[O:12][CH2:11][C:10]2[C:15]([N:17]3[C:29](=[CH:30][C:9]1=2)[C:28]1[N:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[CH:20][C:19]=1[CH2:18]3)=[O:16].S(=O)(=O)(O)O.OO>O>[CH3:1][CH2:2][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:27]=[C:28]2[C:19]=1[CH2:18][N:17]1[C:15](=[O:16])[C:10]3[CH2:11][O:12][C:13]([C@:8]([OH:31])([CH2:7][CH3:6])[C:9]=3[CH:30]=[C:29]12)=[O:14]
Reactant: CCC(=O)O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CCc1c2c(nc3ccccc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Ferrous sulfate heptahydrate (1.20 g, 4.31 m-mol) and propionic acid was dissolved in water (15 ml). Camptothecin (300 mg, 0.862 m-mol) was suspended in the solution and dissolved therein by addition of concentrated sulfuric acid (6 ml) in small portions. To this solution was added dropwise under ice-cooling and agitation a 30% aqueous solution of hydrogen peroxide (1 ml, 9.81 m-mol) in small portions over the period of about 10 minutes. After addition of the hydrogen peroxide, the agitation was continued for 16 hours at room temperature. The reaction mixture was diluted with ice water (300 ml) and extracted with chloroform (400 ml). The chloroform layer was dried with magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to column chromatography (chloroform) through silica gel (10 g) to effect separation and purification of the product whereby 73 mg (22.5 g) of the objective compound were obtained as a yellow white solid.