Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.[OH:32][C@H:33]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:20][CH2:21][N:22]([C:34](=[O:35])[C@H:33]([OH:32])[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:23][CH2:24]1
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2cc(F)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.61 mmol) in CH2Cl2 (5 mL) was added triethylamine (170 μL, 1.22 mmol) followed by the addition of (R)-2-hydroxy-4,4-dimethylpentanoic acid (116 mg, 0.79 mmol), then HATU (301 mg, 0.79 mmol). An additional 3 mL of CH2Cl2 were added, and the reaction was stirred for 3 h. After quenching with water, the mixture was extracted twice with CH2Cl2. The organic phase was dried over MgSO4 and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes yielded (R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one (240 mg, 86%). m/z: M+1 obs=453.5; tR=3.19 minutes 1H NMR (400 MHz, DMSO-d6) δ 8.46 (m, 1H), 8.01 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.96 (m, 2H), 4.89 (d, J=7.1 Hz, 1H), 4.45 (m, 1H), 3.97 (m, 4H), 3.76 (m, 4H), 1.56 (m, 1H), 1.42 (m, 1H), 0.97 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](C(Br)C)[N:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:11]([CH3:12])[O:10][C:8](=[O:9])[C:7]=12
Reactant: CCOC(=O)c1c(Cl)ccnc1C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1OC(=O)c2c(Cl)ccnc21

Procedure:
A mixture of ethyl 4-chloro-2-(1-bromoethyl)nicotinate (7.45 g) and sodium bicarbonate (4.00 g) in 50 ml of DMSO is heated at 120°, under nitrogen, for 2 hours, after which it is cooled, diluted with water, filtered and extracted with ether. The combined organic layers are washed with water and concentrated. The residue is taken into ethyl acetate, washed with brine, dried, concentrated and purified by flash chromatography to give 4-chloro-7-methylfuro-[3,4-b]-pyridin-5-(7H)-one, which is then reacted with N-bromosuccinimide and 2,2'-azobis(2-methylpropionitrile), as above, to give 7-bromo-4-chloro-7-methylfuro-[3,4-b]-pyridin-5-(7H)-one.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH2:7][C:6]2[C:8]([CH3:20])=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Br[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([Cl:30])[CH:24]=1>>[Cl:30][C:25]1[CH:24]=[C:23]([N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]4[O:4][C:3]([CH3:21])([CH3:2])[CH2:7][C:6]=4[C:8]=3[CH3:20])[CH2:19][CH2:18]2)[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: Cc1ccc(Br)cc1Cl
Agent: Cl
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1Cl
Yield: 53.4 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloric acid salt (311 mg, 1.00 mmol) synthesized in Reference example 147 and 4-bromo-2-chloro-1-methylbenzene (308 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 213 mg (yield 58%).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.I[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=[N+]([O-])c1ccc(CCI)cc1
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one (20 mg, 0.081 mmol) in DMF (1 mL) was added 1-(2-Iodoethyl)-4-nitrobenzene (27 mg, 0.097 mmol) and K2CO3 (45 mg, 0.32 mmol). The mixture was allowed to stir at RT for 16 hours. LC showed product formation. The desired product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 396 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: CCc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 2-ethylpyrazolo[1,5-a]pyridine (80 mg) dissolved in tetrahydrofuran (1 mL) was added n-butyllithium (1.6M hexane solution: 0.58 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was further stirred for 30 minutes at the same temperature. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) in tetrahydrofuran (0.5 mL) was added dropwise to the reaction mixture, and stirring was continued for 30 minutes. After raising the temperature to room temperature and adding water to the reaction mixture, extraction was performed with ethyl acetate and the organic extract was washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (90 mg) was obtained as a light brown oil from the n-hexane:ethyl acetate (20:1) fraction.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:36]3[CH2:37][CH2:38][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])=[CH:18]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-3-(1H-Indol-3-yl)-propionic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=103-107° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].CS([C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:19]2[NH:20][CH:21]=[CH:22][C:23]=2[N+:24]([O-:26])=[O:25])[CH:6]=1)[CH3:1]
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCNc2[nH]ccc2[N+](=O)[O-])c1
Yield: 15 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (0.325 g) and 2-methylsulphinyl-3-nitropyrrole (0.25 g) was refluxed in ethanol (12 ml) over 6 days. The solution was evaporated to dryness and the residue was chromatographed on silica gel eluted with 10% methanol/chloroform to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-3-nitropyrrole (0.072 g) as a yellow solid m.p. 90°-95° C. dec.
Reaction SMILES: [H][H].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[N:26]O)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(O)C.O1CCCC1.[Ni]>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([NH2:26])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1ccc2ccccc2n1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3ccc4ccccc4n3)cccc21
Temperature: 60 °C

Procedure:
In a 100 mL autoclave, dissolve 0.9 g of equimolecular mixture of the Z and E isomers of 4-(quinolin-2-yl)-fluoren-9-one oxime, obtained in Stage 3, in a mixture of 40 mL of ethanol and 40 mL of tetrahydrofuran, add a spatula tip of Raney nickel, then submit to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° C. for 2 hours. After cooling, filter the catalyst on Celite and concentrate the filtrate at reduced pressure. After purification by flash chromatography on silica gel (20-40 μm), eluting with a mixture of dichloromethane and methanol (95-05 by volume), we obtain 0.72 g of 4-(quinolin-2-yl)-9H-fluoren-9-(R,S)-yl-amine in the form of a white meringue with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]=[O:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCC[CH2:21]1.C[Mg]Br.C(OCC)C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]([OH:19])[CH3:21])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2ncccc2nc1-c1cccc(F)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirring mixture of 2-(3-fluorophenyl)-1,5-naphthyridine-3-carbaldehyde (0.0293 g, 0.116 mmol) in tetrahydrofuran (2.00 mL, 0.116 mmol) was added methylmagnesium bromide 3M in diethyl ether (0.0581 mL, 0.174 mmol) dropwise at 0° C. and the mixture was allowed to warm to room temperature with stirring. After 2.5 h, the reaction was quenched with saturated aq. NH4Cl (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to give 1-(2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)ethanol as a colorless syrup: LC-MS (ESI) m/z 268.9 [M+H]+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.[CH2:23]([NH2:25])[CH3:24]>C(O)C.C1COCC1>[CH2:23]([NH:25][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1)[CH3:24]
Reactant: CCN
Reactant: N#Cc1ccc2c(c1)COC2(CCCI)c1ccc(F)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 56.7 %

Procedure:
To a stirred solution of 1-(3-iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (12.9 g, 30 mmol, 8% pure) in ethanol (150 mL) was added a solution of ethylamine (20.3 g, 450 mmol) in THF (50 mL) portionwise, and the mixture was stirred over night. The solution was evaporated, and was dissolved/suspended in water. The pH was adjusted to 12 using aqueous sodium hydroxide solution (2M) and was extracted with ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. This oil was purified by silica chromatography using 50% v/v ethyl acetate/heptane as eluent, followed by 10% v/v triethylamine/40% v/v ethyl acetate/heptane followed by 20% v/v triethylamine/ethyl acetate to give the title compound (5.52 g, 57%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.05 (t, 3H), 1.2-1.6 (m, 2H), 2.15 (ddd, 1H), 2.24 (ddd, 1H), 2.57 (q, 2H) 2.58 (t, 2H), 5.12 (dt, 1H), 5.20 (dt, 1H), 7.00 (t, 2H), 7.38 (d, 1H), 7.42 (dd, 2H), 7.49 (s, 1H), 7.58 (ddt, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1)#[N:22]
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2ccc(C#N)cc2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 4-bromomethyl-benzonitrile in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-propionamide as a white solid; MS: m/e=311 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:8][C:9]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=1[NH2:11])=[O:5])[CH3:2].[Cl:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](O)=[O:48])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23>C(O)(=O)C.C(OCC)(=O)C>[Cl:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](=[O:48])[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:15][C:9]=3[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23
Reactant: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1N)C(=O)OCC
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23)C(=O)OCC
Yield: 78.3 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 2-(3,3-diethoxycarbonylpropyl)-4-tert-butoxycarbonylaminomethylaniline (559 mg, 1.37 mmol) and (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (445 mg, 1.51 mmol) to give 735 mg of the title compound after silica gel column chromatography with 0.3% acetic acid/ethyl acetate (78%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.C([CH:31]([C:35]1[S:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[N:37][CH:36]=1)[C:32]([O-:34])=[O:33])C=C>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:25])([F:27])[F:26])[CH:5]=[CH:4][C:3]=1[CH2:2][O:46][C:43]1[CH:42]=[CH:41][C:40]([C:38]2[S:39][C:35]([CH2:31][C:32]([OH:34])=[O:33])=[CH:36][N:37]=2)=[CH:45][CH:44]=1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: C=CCC(C(=O)[O-])c1cnc(-c2ccc(O)cc2)s1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ncc(CC(=O)O)s3)cc2)ccc(C(F)(F)F)c1O
Yield: 9 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (11-7), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (314 mg, 0.69 mmol) obtained in Example (28-5) and allyl[2-(4-hydroxyphenyl)-1,3-thiazol-5-yl]acetate (190 mg, 0.69 mmol) obtained in Example (30-2), the title compound was obtained as a colorless powder (33 mg, three-step total yield: 9%).
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1.Br[C:25]1[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=1>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:14][C:12]1[CH:11]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][N:17]([C:25]3[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=3)[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: CC(=O)NCc1ccc(Br)cc1C
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
Sodium tert-butoxide (0.3 g), Tris(dibenzylidene acetone)dipalladium(0) (chloroform adduct) (0.04 g) and xantphos (0.07 g) was added to the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.59 g) and N-(4-bromo-2-methylbenzyl)acetamide (0.5 g) in toluene under argon atmosphere, and the mixture was heated with stirring at 80° C. for 5 hours. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methylbenzyl}acetamide (0.6 g). 1H-NMR (CDCl3) δ: 2.13-2.18 (6H, m), 2.51-2.53 (1H, m), 2.81-2.83 (1H, m), 3.45-3.56 (2H, m), 3.75-3.78 (1H, m), 4.01-4.04 (1H, m), 4.25 (1H, s), 4.57 (1H, s), 6.40-6.44 (2H, m), 6.93-6.96 (1H, m), 7.30-7.38 (3H, m)
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]2[O:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)CC2C=CC=CC=2)[OH:10])=[CH:4][C:3]=1[Cl:38].Cl.C(O)C>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([Cl:38])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]2[O:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2nc3ccccc3o2)Cc2ccccc2)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2nc3ccccc3o2)cc1Cl

Procedure:
A solution of 4-amino-3,5-dichloro-α-[[[6-[2-(2-benzoxazolyl)ethoxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol (1.09 g) in ethanol (25 ml) containing conc. hydrochloric acid-ethanol (1:9, 1.78 ml) was added to a pre-hydrogenated suspension of 10% palladium on carbon (50% aqueous paste, 0.65 g) and hydrogenated at room temperature and pressure, then filtered through hyflo and evaporated in vacuo. The residue was partitioned between 8% sodium bicarbonate (25 ml) and ethyl acetate (50 ml) and the organic phase dried and evaporated in vacuo to a semi solid. Purification by FCC over silica (Merck 60) eluting with System B (97:2:1→94:5:1) afforded the title compound as a gum, which crystallised after trituration with hexane to a white solid (613 g) m.p. 85°-87°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22].C(N(CC)CC)C>CN(C)C=O>[O:22]=[S:21]1(=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30](=[O:31])[N:20]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: COc1cccc2c1OC(CN)CC2
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1OC(CNCCCCN1C(=O)c3ccccc3S1(=O)=O)CC2
Yield: 21.5 %

Procedure:
5.3 g (0.027 mol) 2-aminomethyl-8-methoxychroman from example 93g, 9.5 g (0.03 mol) N-(4-bromobutyl)saccharin, 3.05 g (0.03 mol) triethylamine and 80 ml dimethylformamide were heated to 50° C. for 4h. Work-up as described in example 93h furnished 16.6 g crude product, which was filtered through 175 g silica with toluene/ethyl acetate. This gave 3.4 g dialkylation product and 7.1 g monoalkylation product. Rechromatography of the monoalkylation product on 230 g silica with toluene/methanol (10:1) gave 2.5 g pure 2-(N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-8-methoxy-chroman.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]2[CH2:30][O:29]2)[N:11]=1.C1COCC1.[CH3:36][NH:37][CH3:38]>C(O)C>[CH3:36][N:37]([CH3:38])[CH2:30][CH:28]([OH:29])[CH2:27][CH2:26][N:12]1[C:13]2=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=[C:18]2[C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[N:11]1
Reactant: Cc1cccc(C)c1Nc1nn(CCC2CO2)c2nc(Nc3ccccc3)ncc12
Reactant: CNC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1Nc1nn(CCC(O)CN(C)C)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 60 mg (0.15 mmol) of N3-(2,6-dimethylphenyl)-1-(2-(oxiran-2-yl)ethyl)-N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 42 (Example 9, Step A) in 4 mL of absolute ethanol was treated with 375 μl (2.0 M, 0.8 mmol) of a THF solution of dimethylamine. The resulting yellow solution was stirred at room temperature for 2.5 h and then heated to 40° C. for an additional 2 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 19:1 grading to CH2Cl2:MeOH, 9:1) to give the title compound 43. 1H-NMR (CD3OD) δ 1.75-1.84 (m, 1H), 1.95-2.05 (m, 1H), 2.19 (s, 6H), 2.26 (s, 6H), 2.27-2.43 (m, 2H), 3.63-3.70 (m, 1H), 4.17-4.31 (m, 2H), 7.00 (t, J=7.4 Hz, 1H), 7.09-7.16 (m, 3H), 7.30 (t, J=8.0 Hz, 2H), 7.75 (dd, J=8.7 Hz, 1.0 Hz, 2H), 8.10 (s, 1H). Mass Spectrum (ESI) m/e=446.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](C(C)(C)C)[CH:8]=[CH:7][C:6]=1[OH:15])(C)(C)[CH3:2].C(OC[N:22](COCC(C)C)C)C(C)C>C1(C)C=CC=CC=1>[O:15]1[C:6]2=[CH:7][CH:8]=[CH:9][CH2:10][CH:5]2[CH2:1][CH2:2][NH:22]1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC(C)COCN(C)COCC(C)C
Solvent: Cc1ccccc1
Product: C1=CCC2CCNOC2=C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 189.8 %

Procedure:
A 1000 ml four-neck flask was initially charged with 206 g of 2,4-di-tert-butylphenol at room temperature in 400 ml of toluene. 203 g of N,N-di(isobutoxymethyl)-N-methylamine from example 1 were added rapidly. The flask contents were stirred at 80° C. for 60 minutes. The solution was concentrated by evaporation at 120° C. and 5 mbar. 260 g of product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[CH:12]=O.[BH4-].[Na+].P(Br)(Br)[Br:17]>C(O)C.CCOCC>[Br:17][CH2:12][C:4]1[S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C=O)sc2ccccc12
Reactant: BrP(Br)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1c(CBr)sc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 3-methoxybenzothiophene-2-carboxaldehyde [3.4 g; J. Chem. Soc. C 779 (1967)] in ethanol (60 ml) was added sodium borohydride (0.34 g). After 10 minutes the solution was poured onto water (200 ml) and extracted with ether (2×50 ml). The ether extracts were washed with water (2×25 ml), dried and then evaporated to the title product as an orange oil. Yield, 3.4 g. 'HNMR (CDCl3, 60 MHz): 2.6 (s, 1H), 3.8 (s, 3H), 4.8 (s, 2H), 7.0-8.0 (m, 4H). This material (1.5 g) was dissolved in ether (20 ml). To the solution cooled in an ice-bath was added phosphorous tribromide (0.7 ml). The mixture was let to stand for 1 hour. The reaction mixture was poured onto ice-water (50 ml) and the ether layer separated, collected, dried and evaporated to obtain the title product as a light yellow oil (yield, 1.4 g). 'HNMR CDCl3, 60 MHz): 4.0 (s, 3H), 5.0 (s, 2H), 7.2-7.8 (m, 4H).