Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([OH:21])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CCOCC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(O)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
A mixture of 3-[4-(3-hydroxy-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (2.83 g, 9.01 mmol), 3-bromo-4-fluorobenzotrifluoride (2.19 g, 9.01 mmol) and 325 mesh potassium carbonate (1.49 g, 10.8 mmol) in dry DMSO (36 mL) is heated to 100° C. and stirred for 5 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 3.45 g (71%) of the title compound. Rf=0.54 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H24O4F3Br 536, found 554 and 556 (M+NH4, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:3]1.[Br:23]Br>CN(C=O)C>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:15])([F:16])[F:14])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: Cn1cc(-c2ccncc2)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: BrBr
Solvent: CN(C)C=O
Product: Cn1c(Br)c(-c2ccncc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A solution of 7-methyl-5-(pyridin-4-yl)-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (130 mg, 0.422 mmol) in DMF (6 ml) was cooled to 0° C. Bromine (0.026 ml, 0.506 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 60 min. The reaction mixture was partitioned between ethyl acetate (40 ml) and a mixture of aqueous (3:1:4, water, sodium bicarbonate solution and 20% w/w sodium thiosulfate solution, 40 ml). The organic phase was separated and washed with water (3×30 ml), brine and concentrated to give the title compound (160 mg, 98%). LCMS RT=0.72 min, [M+H+(79Br)]=387.0, [M+H+(81Br)]=389.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:34]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc2c(C)cc(=O)oc2c1
Yield: 91.7 %

Procedure:
35.2 g (0.2 mole) of 7-hydroxy-4-methyl-coumarin, 27.6 g (0.2 mole) of potassium carbonate, 55.4 g (0.2 mole) of 1-bromotetradecane and 600.0 ml of dry dimethylformamide are stirred in a steam bath overnight. The mixture is cooled and extracted into 1.5 liters of diethyl ether. The ether layer is washed 5 times with saturated saline. It is dried (Na2SO4) and evaporated. The ether is replaced with 800 ml of hexane. The mixture is recrystallized therefrom, yielding 68.3g (92%) of 7-tetradecyloxy-4-methyl-coumarin, m.p. 61°-62° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].O[C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:8][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]34[CH2:27][CH2:26][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:24][CH2:23]3)[CH2:28][CH2:29]4)=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/C(=O)O
Reactant: CCCCCC12CCC(c3ccc([C@H]4CC[C@H](O)CC4)cc3)(CC1)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)O[C@H]1CC[C@H](c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (0.22 g, 1.1 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.10 g, 0.9 mmol), 1-[4-(trans-4-hydroxycyclohexyl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.32 g, 0.9 mmol), 4-(dimethylamino) pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate is evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallization from ethanol to yield the desired ester (0.26 g, 64%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([CH3:23])([OH:22])[CH2:11][CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[N:15]=[C:14]2Cl)=[CH:4][CH:3]=1.[H-].[Na+]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2([CH3:23])[O:22][C:14]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:13]3[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Product: CC1(COc2ccc(Br)nc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 66 %

Procedure:
Ring closure of alcohol 151 with NaH (1.5 equiv.) as in Example 2AA, followed by chromatography of the product on silica gel, eluting with 0-50% EtOAc/petroleum ether (foreruns) and then with 0-2% MeOH/CH2Cl2, gave 7-{[(6-bromo-3-pyridinyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (152) (66%) as a light yellow solid: mp (CH2Cl2/hexane) 170-171° C.; 1H NMR (CDCl3) δ 8.06 (dd, J=3.1, 0.3 Hz, 1H), 7.46 (s, 1H), 7.40 (dd, J=8.7, 0.3 Hz, 1H), 7.11 (dd, J=8.7, 3.2 Hz, 1H), 4.21-4.07 (m, 4H), 2.52 (ddd, J=14.5, 8.1, 6.3 Hz, 1H), 2.24 (dt, J=14.5, 5.7 Hz, 1H), 1.60 (s, 3H). Anal. (C13H13BrN4O4) C, H, N.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.CON(C)[C:20](=[O:23])[CH2:21][CH3:22]>O1CCCC1.CCOCC>[F:11][C:10]1[C:3]2[CH:2]=[C:6]([C:20](=[O:23])[CH2:21][CH3:22])[S:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(=O)N(C)OC
Reactant: Fc1cccc2scc(Br)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)c1cc2c(F)cccc2s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A solution of 3-bromo-4-fluorobenzo[b]thiophene (3.0 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at −60-−70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 6.75 ml) in ether (30 ml), then the mixture was stirred at −70° C. for 30 minutes. A solution of N-methoxy-N-methylpropionamide (1.31 g) in tetrahydrofuran (10 ml) was added dropwise at −70° C. over 10 minutes, then the mixture was stirred at −70° C. for 5 hours and allowed to stand at ambient temperature for 12 hours. The mixture was quenched by the addition of saturated aqueous ammonium chloride solution (40 ml), then the organic layer was separated, washed with saturated aqueous sodium chloride solution (40 ml), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(4-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.54 g) as a colourless solid which was used without further purification.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[CH:12][C:11]=1[OH:18])(=[O:8])[O:5]CC)C>Cl>[OH:18][C:11]1[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:10]=1[CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(Cc1cc(C=O)ccc1O)OCC
Agent: Cl
Product: O=Cc1ccc(O)c(CP(=O)(O)O)c1

Procedure:
0.1 mole 2-Hydroxy-5-formylbenzylphosphonic acid diethyl ester was refluxed for 3 hours with 100 ml 6N HCl. Product was separated out while it was being formed. The reaction solution was cooled in the refrigerator and the product was isolated on a buchner funnel and washed with cold water. mp 252°-253° C.
Reaction SMILES: [CH3:1][N:2]([C:13]1[C:18]([F:19])=[C:17](F)[N:16]=[C:15]([F:21])[C:14]=1[F:22])[C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=1[OH:39])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(OCC)(=O)C>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=1[O:39][C:17]1[C:18]([F:19])=[C:13]([N:2]([CH3:1])[C:3]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:14]([F:22])=[C:15]([F:21])[N:16]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(N(C)c2c(F)c(F)nc(F)c2F)CCCC1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(N(C)c2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)CCCC1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of 4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-2,3,5,6-tetrafluoropyridine (0.89 g, 2.8 mmol) in acetonitrile (30 mL) was added 2-benzyloxy-5-cyanophenol (0.63 g, 2.8 mmol) and cesium carbonate (1.2 g, 3.6 mmol). The resultant mixture was stirred at 60° C. for 1 day. The mixture was then cooled to ambient temperature and poured into 100 mL of water and 100 mL of ethyl acetate. The aqueous layer was separated and extracted with another 100 mL of ethyl acetate. The combined organic extracts were washed with 1M aqueous KOH solution (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. Purification by flash chromatography on silica gel afforded 0.87 g (60% yield) of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile, a compound of formula (G), as a clear, colorless oil: NMR (CDCl3) 7.6-7.1 (m, 8), 5.2 (s, 2), 4.2 (q, 2), 3.1 (s, 3), 2.3-1.6 (m, 8), 1.3 (t, 3) ppm.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[BH-](O[C:24](=O)[CH3:25])OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:8]1[CH:9]=[CH:10][N:11]=[C:24]1[CH2:25][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1ccnc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
N-Boc-piperazine (0.930 g, 5.0 mmol, 1.1 eq) was dissolved in 1,2-DCE (14 mL). To this solution, 1-methyl-2-imidazolecarboxy aldehyde (0.50 g, 4.54 mmol, 1 eq) was added followed by the portionwise addition of sodium triacetoxyborohydride (1.350 g, 6.36 mmol, 1.4 eq). The mixture was stirred at room temperature for 4 h and was then washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), and the solvent removed in vacuo. The crude mixture was redissolved in 18 mL of DCM and gently stirred overnight in the presence of PS-isocyanate (2 g, loading: 1.58 mmol/g). The mixture was filtered off, and the resin washed with DCM (2×10 mL). The solvent was removed in vacuo and the resulting mixture was purified by column chromatography on a Biotage SP1 system eluting with methanol (1-8%) in dichloromethane to give the title compound as a off-white solid (0.450 g, 32%); 1H-NMR (500 MHz, CDCl3): δ 1.40 (s, 9H, C(CH3)3), 2.30-2.40 (m, 4H, piperazine N(CH2)2), 3.30-3.38 (m, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 3.67 (s, 3H, imidazole Me), 6.81 (s, 1H, imidazole 4-H), 6.90 (s, 1H, imidazole 5-H); GC-MS (ESI, m/z): Rt=4.62 min, 281.1-[(M+H)+, 100%].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:33][CH3:34])[CH:31]=[CH2:32]>CN(C)C(=O)C>[CH2:30]([N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH:31]=[CH2:32]
Reactant: C=CCNC
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: C=CCN(C)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-{4-[4-(allyl-methyl-amino)-butoxymethyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS: 491 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[N:6]1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1
Reactant: COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(C)(C)Cn1ccc(N)n1
Yield: 70.9 %

Procedure:
In a Parr shaker bottle was placed 1-(2-methoxy-2-methyl-propyl)-3-nitro-1H-pyrazole (1.33 g, 6.68 mmol), 10% palladium on activated carbon (135 mg) and ethanol (50 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 2 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentration in vacuo with silica gel (3 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 5% methanol/ethyl acetate) to afford 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (802 mg, 71%) as a colorless oil: ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2208; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 6H, 2×CH3), 3.13 (s, 3H, OCH3), 3.80 (s, 2H, NCH2), 4.48 (brs, 2H, NH2), 5.38 (d, J=2.3 Hz, 1H, Ar), 7.21 (d, J=2.3 Hz, 1H, Ar).
Reaction SMILES: O[C:2]1([C:26]2[C:35]([OH:36])=[CH:34][C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[CH:27]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[C:9]=2[O:11][CH3:12])[N:4]([CH2:15][C:16]2[O:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[C:3]1=[O:25].ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:36][C:35]1[C:26]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[C:9]=3[O:11][CH3:12])[N:4]([CH2:15][C:16]3[O:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[C:3]2=[O:25])=[CH:27][C:28]2[O:33][CH2:32][CH2:31][O:30][C:29]=2[CH:34]=1
Reactant: COc1ccc2c(c1OC)C(O)(c1cc3c(cc1O)OCCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: COc1ccc2c(c1OC)C(c1cc3c(cc1O)OCCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (83%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ6.86 (d, J=8.5 Hz, 1H), 6.71-6.67 (m, 1H), 6.66-6.60 (m, 2H), 6.32-6.25 (m, 2H), 5.11 (s, 1H), 4.94-4.76 (m, 2H), 4.23-4.07 (m, 5H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCN(c2ccnc(Cl)c2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 8-(2-chloropyridin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (1.26 g, 4.95 mmol) in acetone (11 mL) was added HCl (2 N, 39.6 mL, 79.1 mmol) and the resulting mixture stirred at 50° C. for 2 hours, then cooled to room temperature. The pH was set to ˜8 by adding solid sodium hydrogen carbonate and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title product (1.03 g, 99%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:31]([O:34][CH2:35]Cl)[CH2:32][CH3:33].O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:35][O:34][CH2:31][CH2:32][CH3:33])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Reactant: CCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 1 h

Procedure:
0.45 g (3.26 mmol) of potassium carbonate was added at 60° C. to a suspension of 0.65 g (2.04 mmol) of 7-benzyl-3-phenylxanthine from stage a) in 20 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 0.29 ml (2.65 mmol) of propoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 1.5 hours. 20 ml of water were then added, the mixture was extracted three times using 24 ml of methyl tert-butyl ether each time, and the combined organic phases were washed twice with 12 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column heptane/ethyl acetate (5/7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>C(Cl)Cl>[Cl:41][CH2:42][C:43]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=1)=[O:44]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 53.2 %

Procedure:
To a suspension of N-[(3-aminophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide (800 mg, 1.84 mmol) in methylenechloride (30 ml) cooled to 0 C was added DIEA (300 mg, 2.32 mmol) followed by chloroacetyl chloride (300 mg, 2.65 mmol). Purification by flush chromatography (eluent 30% acetone/DCM) afforded 500 mg (53%) of 2-chloro-N-(3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)acetamide an off-white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](C3CCCCO3)[CH:28]=2)=[CH:12][C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:35][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[CH:14]=[C:15]([F:16])[C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)cc1F
Yield: 53.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (100 mg, 0.171 mmol) prepared in Example 94a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol (1.0 mL), to yield the title compound (40 mg, 54%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:31]([CH2:30][CH2:29][CH2:28][CH2:27][Cl:26])(=[O:33])=[O:32])[CH2:24][CH2:25]2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 59) and 4-chloro-butane-1-sulfonyl chloride (Example 254) in an analogous manner as described in Example 177. HR-MS (ES, m/z) calculated for C21H27N5O4SFCI [(M+H)+] 500.1532, observed 500.1529.
Reaction SMILES: C1([C@@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)N2CC[C@](CC(O)(C)C)(C3C=CC=CC=3)OC2=O)CC1.Br[C:39]1[CH:44]=[CH:43][C:42]([C@H:45]([CH:64]2[CH2:66][CH2:65]2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])=[CH:41][CH:40]=1.Br[C:68]1[CH:69]=[N:70][C:71]([CH3:74])=[N:72][CH:73]=1>>[CH:64]1([C@@H:45]([C:42]2[CH:43]=[CH:44][C:39]([C:68]3[CH:69]=[N:70][C:71]([CH3:74])=[N:72][CH:73]=3)=[CH:40][CH:41]=2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])[CH2:66][CH2:65]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Reactant: Cc1ncc(Br)cn1
Agent: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Product: Cc1ncc(-c2ccc([C@H](C3CC3)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 5-bromo-2-methyl-pyrimidine following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.28 min; Mass spectrum (ESI+): m/z=472 [M+H]+.