Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:64][CH2:65][CH:66]1[CH2:68][CH2:67]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:66]1([CH2:65][NH:64][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH2:68][CH2:67]1
Reactant: NCC1CC1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCCC2)c2ccc(NCC3CC3)cc2n1
Yield: 30 %

Procedure:
A suspension of 1.01 g (3 mmol) of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline, 0.186 g (0.3 mmol) rac BINAP, 33.7 mg (0.15 mmol) of palladium(II)acetate and 0.87 g (9 mmol) of sodium tert-butylate in toluene (25 ml) was treated at RT with 0.427 g (6 mmol) of aminomethyl cyclopropane and then heated to reflux under an argon atmosphere for 20 h. The reaction mixture was then filterd by suction over fiberglass filter paper and the filtrate was partitioned between EtOAc and water. The layers were separated, the organic layer dried over sodium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (15:1:0.2) as eluent. Combination of the purified fractions and concentration in vacuo gave 253 mg (30%) of the desired cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-amine as light yellow foam. ISP mass spectrum, m/e: 282.2 (M+1 calculated for C18H23N3O: 282).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:8]([C:18]([OH:20])=[O:19])=[CH:7][CH:6]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.Cl>ClCCCl>[C:24]([CH2:23][CH2:22][C:21]([C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[C:8]([C:18]([OH:20])=[O:19])=[CH:7][CH:6]=[CH:5][C:17]=3[CH2:16]2)=[CH:11][CH:12]=1)=[O:27])([OH:26])=[O:25]
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc2c(c1)Cc1cccc(C(=O)O)c1-2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a dry argon-purged round bottom flask anhydrous AlCl3 (26.9 g, 0.202 mol) was suspended in anhydrous 1,2-dichloroethane (60 mL). 4-Fluorenecarboxylic acid (10.0, g, 0.048 mol) was added to the suspension. The reaction flask was placed in a room temperature bath and succinic anhydride (5.72 g, 0.057 mol) was carefully added. The reaction was stirred for five hours and then cooled to 0° C. The reaction was very carefully quenched by the slow portion-wise addition of 3 M HCl (Caution! The reaction can react violently when HCl is added too rapidly.) The final well mixed suspension was acidic and not reactive to additional HCl solution. The organic solvent was removed at reduced pressure and the product was filtered and washed well with water. The crude product was dissolved in warm NaOH solution (approximately ≦1 M NaOH), filtered and precipitated with the addition of concentrated HCl. The product was filtered washed with water and then dried at reduced pressure in the presence of P2O5. The product was a pale yellow solid (14.3 g, 97%). 1H-NMR (d6-DMSO): δ (ppm) 8.4 (d, 1H, Ar); 8.2 (s, 1H, Ar); 8.0 (d, 1H, Ar); 7.8 (m, 2H, Ar); 7.5 (t, 1H, Ar); 4.1 (s, 2H, CH2); 2.6 (t, 2H, CH2) 2.5 (under DMSO, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:24](=[O:25])[N:23]([O:26][CH3:27])[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:24](=[O:25])[N:23]([O:26][CH3:27])[C:14]2[N:15]=[C:16]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[N:17]=[CH:18][C:13]=2[CH:12]=1
Reactant: CN(C)CCN
Reactant: COn1c(=O)c(-c2cc([N+](=O)[O-])ccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: CC(C)O
Product: COn1c(=O)c(-c2cc([N+](=O)[O-])ccc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 100 °C

Procedure:
6-(2-Chloro-5-nitrophenyl)-8-methoxy-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (4.87 mmol), N,N-dimethylethane-1,2-diamine (11.3 mmol), and conc. aq. hydrochloric acid (2.0 mL) were placed in a microwave vessel and dissolved in 2-propanol (18 mL). The mixture was heated with microwave irradiation in a sealed vessel at 100° C. for 15 min. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc. The organic layer was washed with water and aqueous buffer (aq. KH2PO4 and NaOH. pH 7.0). The aqueous layer was backextracted with EtOAc (4×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give solid 6-(2-chloro-5-nitrophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one that was used without furoom temperatureher purification (53%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:25])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:24])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:15])[CH2:6][CH2:5]2.[O:26]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:26][C:7]([CH3:24])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:25])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCCCO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCCCCO)=C(C)C1=O
Yield: 59.8 %

Procedure:
Oxidation as described in protocol B, using 64.2 mg (0.183 mmol) of 6-hydroxy-N-(6-hydroxyhexyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 230 mg CAN (0.419 mmol) yielded 40 mg of 2-hydroxy-N-(6-hydroxyhexyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:22]1([CH3:30])[CH:27]=[CH:26][CH:25]=[C:24]([Mg]Br)[CH:23]=1.O1CCCC1>C(OCC)C>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])=[CH:10][C:3]=1[C:4]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH3:30])[CH:23]=1)=[O:5]
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)c1
Temperature: 0 °C

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (2.0 g, 6.4 mmol) in diethyl ether (50 ml) was added dropwise 1.0 M solution of m-tolylmagnesium bromide in tetrahydrofuran (30 ml, 30 mmol) under ice-cooling over 30 min. Ice water (250 g) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone as a mixture. To a solution of the obtained mixture (1.4 g) of (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone and 5-methyl-3-oxohexanenitrile (0.60 g, 4.7 mmol) in toluene (50 ml) was added methanesulfonic acid (0.38 g, 4.0 mmol), and the mixture was heated under reflux for 6 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the organic layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained crude crystals were recrystallized from n-hexane-ethyl acetate to give 6-hydroxy-2-isobutyl-4-(3-methylphenyl)quinoline-3-carbonitrile (0.73 g, yield 36%) as pale-yellow crystals.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[I:11]I>C(O)C>[I:11][C:7]1[CH:8]=[C:1]([O:9][CH3:10])[C:2]([O:3][CH3:4])=[CH:5][CH:6]=1
Reactant: II
Reactant: COc1ccccc1OC
Solvent: CCO
Product: COc1ccc(I)cc1OC
Yield: 70 %

Procedure:
A solution of veratrole (28.0 ml, 0.22M) in 95% ethanol (75 ml) was heated to 60° C. and, while stirring, was treated with iodine (50 g, 0.197M) and yellow mercuric oxide (30.0 g, 0.1385M). The iodine and mercuric oxide were added alternately in small portions over a period of 1.5 hours. After the addition was complete, the cooled mixture was filtered through Celite and concentrated. The residue was taken up in Et2O and again filtered. The Et2O solution was washed with solutions of sodium thiosulfate, 2N NaOH, saturated NaCl, dried over anhydrous K2CO3 and evaporated. The residue was distilled under reduced pressure to give 40.88 g, bp 110°-112° C. (2 mm) pure 4-iodoveratrole [70% yield, literature: Gutzke et al., J. Org. Chem. 22, 1271 (1957), bp 80°-85° C. (1 mm)]. NMR (CDCl3) δ 3.80 ppm (s, 6H, (2x) OCH3), 6.57 (d, 1H, ArH6), 7.20 (m, 2H, ArH3 and ArH5).
Reaction SMILES: [OH:1][C:2]([C:7]1[NH:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][C:15]([O:27][CH3:28])=[C:16]3[C:20]([C:21](=[O:26])[C:22]([O:24]C)=[O:23])=[CH:19][NH:18][C:17]=23)[CH:8]=1)([CH2:5][CH3:6])[CH2:3][CH3:4].CO.C(=O)([O-])[O-].[K+].[K+].Cl>O>[OH:1][C:2]([C:7]1[NH:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][C:15]([O:27][CH3:28])=[C:16]3[C:20]([C:21](=[O:26])[C:22]([OH:24])=[O:23])=[CH:19][NH:18][C:17]=23)[CH:8]=1)([CH2:3][CH3:4])[CH2:5][CH3:6]
Reactant: CCC(O)(CC)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)OC)c[nH]c23)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(O)(CC)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)O)c[nH]c23)n[nH]1
Reaction time: 1 h

Procedure:
To a flask containing methyl 2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.066 g, 0.171 mmol) was added MeOH (1 mL) and Water (1 mL). To the mixture was added potassium carbonate (0.118 g, 0.854 mmol). After 1 h, the mixture was made acidic (pH=1) by adding 1N HCl. No precipitate formed, so the solvent was removed under reduced pressure. The crude mixture containing 2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid was carried forward to the next step with no further purification. LCMS: m/e 373.22 (M+H)+, ret time 1.723 min (method 4).
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.Cl.[CH3:10][O:11][NH2:12].C([O-])(O)=O.[Na+]>C(O)C>[CH3:10][O:11][N:12]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[Cl:1]
Reactant: CON
Reactant: O=C1CCCCC1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCCCC1Cl
Temperature: 22.5 °C

Procedure:
3.0 g (22.6 mmol) of 2-chlorocyclohexanone were initially charged in 30 ml of ethanol, and 1.9 g (22.6 mmol) of O-methyl hydroxylamine hydrochloride were added with stirring at from 20 to 25° C. This mixture was stirred for about 20 hours at from 20 to 25° C., adjusted with sat. NaHCO3 solution to a pH between 7 and 8 and extracted with ethyl acetate. After washing with sat. NaCl solution, the combined organic phases were dried and then freed from the solvent. The title compound (3.4 g) was directly used further.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH2:25][CH3:26])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCc1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CCc1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 81 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-ethyl-phenol (32 mg, 0.26 mmol) to give the title compound (49 mg, 80%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10](O)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:10][OH:11])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with AcOEt. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/AcOEt, 1:1) Rf 0.43, 1H NMR (400 MHz, chloroform-d) 8 ppm 1.61-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.53 (m, 1H), 3.57 (d, 2H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[O:19][CH3:20].C1COCC1>C(O)C>[F:1][C:2]1[CH:24]=[C:23]([CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[O:19][CH3:20])[NH2:25]
Reactant: COc1cc(C#Cc2ccccn2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CCc2ccccn2)ccc1Oc1ccc(N)cc1F

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by 2-{[4-(2-fluoro-4-nitrophenoxy)-3-methoxy phenyl]ethynyl}pyridine (0.23 mmol; 84 mg) and THF by ethanol, the title compound was obtained as a clear oil (68%, 53 mg) after purification on preparative TLC (cyclohexane/ethyl acetate: 6/4).
Reaction SMILES: [NH2:1][C:2]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[C:42](Cl)(=[O:44])[CH3:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:38]([C:2]([NH:1][C:42](=[O:44])[CH3:43])([C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])[CH2:40][CH3:41])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CCC(N)(CC)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)(NC(C)=O)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1

Procedure:
A solution of 2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.100 g, 0.178 mmol), acetyl chloride (0.014 g, 0.178 mmol) and DIEA (0.069 g, 0.534 mmol) were stirred at room temperature in DCM (3 ml) for 2 hours. Solvent was removed and compound was purified by RP-HPLC to yield 0.072 g (67%). 1H NMR (400 MHz, CDCl3) 7.67 (m, 1H), 7.40-7.29 (m, 2H), 7.18 (m, 2H), 7.09 (m, 1H), 6.99 (m, 2H), 4.60 (m, 1H) 4.04 (br, 2H), 3.32-3.23 (m, 4H), 2.74 (m, 2H), 2.57 (s, 3H), 2.36 (m, 2H), 2.20 (m, 2H), 2.01 (s, 3H), 1.92 (m, 6H), 1.82-1.63 9 (m, 10H), 0.78 (br, 5H). ES-LCMS m/z 602 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 120 °C
Yield: 11.5 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added ethanesulfonyl chloride (19 μl, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (3 mg, 11%). 1H NMR (300 MHz, DMSO-d6): δ 0.98 (d, J=6.62 Hz, 6 H) 1.22 (t, J=7.35 Hz, 3 H) 1.58 (m, 2 H) 1.70 (m, 1 H) 3.20 (q, J=7.35 Hz, 2 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=8.82, 2.57 Hz, 1 H) 7.65 (d, J=2.57 Hz, 1 H) 7.74 (d, J=9.19 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.60, 1.65 Hz, 1 H) 10.35 (s, 1 H) 14.15 (s, 1 H). MS (ESI−) m/z 518 (M−H)−.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]2[CH2:20][O:19]2)[CH:11]=1)(=O)C1C=CC=CC=1.[C:21]1([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.CS(C)=O>[OH:19][CH:18]([CH2:20][NH:42][CH:39]1[CH2:40][CH2:41][N:36]([C:34]2[C:35]3[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:28][S:29][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:37][CH2:38]1)[CH2:17][O:16][C:12]1[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Oc1cccc(OCC2CO2)c1)c1ccccc1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Oc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c1
Yield: 20 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 3:1, 24 h), using 150 μmol 3-(oxiran-2-ylmethoxy)phenyl benzoate and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine. The benzoic acid moiety was already lost during purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) and subsequent prep. HPLC (reversed phase) to give the title compound with 20% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]([CH2:9][CH2:10][OH:11])[O:7][CH2:8][C:4]=2[CH:3]=1.[Si:14](OCC[C@H]1C2C=CC(Br)=CC=2CCO1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[C:17]([Si:14]([O:11][CH2:10][CH2:9][CH:6]1[C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=2[CH2:8][O:7]1)([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: OCCC1OCc2cc(Cl)ccc21
Product: CC(C)(C)[Si](C)(C)OCCC1OCc2cc(Cl)ccc21

Procedure:
Prepared from 2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethanol, as described for the preparation of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl tert-butyl(dimethyl)silyl ether, to yield tert-butyl-[2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethoxy]-dimethylsilane.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[N:18]1([CH2:24][CH:25]([OH:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([CH2:24][C:25](=[O:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccccc1OCC(O)CN1CCOCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(COc1ccccc1[N+](=O)[O-])CN1CCOCC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A five liter round bottom flask was charged with 63.8 ml (0.45 mole) of trifluoroacetic anhydride and 400 ml of MDC under nitrogen. The resulting solution was cooled to -65° C. with a dry ice bath, treated with 42.6 g (0.54 mole) of dimethylsulfoxide over a period of 15 minutes,. stirred for 30 minutes, and then treated with a solution of 90 g (0.32 mole) of 2-[3-(4-morpholinyl) -2-hydroxy-1-propyloxy]nitrobenzene in 200 ml of MDC over a 35 minute period. The reaction mixture was stirred for 30 minutes, quenched with 261 ml of diisopropylethylamine, the reaction temperature allowed to rise to -10° C. and the mixture treated with one liter of diethyl ether. The pale yellow solid which separated was collected by filtration, slurried in 1.5 liters of diethyl ether and the product collected and dried to give 73.7 g of 2-[3-(4-morpholinyl) -2 -keto-1-propyloxy]nitrobenzene.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH:14]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)#[N:9]>ClCCl>[NH:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[C:10]([CH:27]=[CH:26][CH:25]=2)[C:8]#[N:9])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cccc(C#N)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(OC2CNC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (10 ml) is added to a solution of tert-butyl 3-(3-cyanophenoxy)azetidine-1-carboxylate a1-43 (260 mg, 0.95 mmol, 1 eq) in dichloromethane (10 ml). The reaction mixture is stirred for 2 hours at room temperature, then concentrated to dryness to afford 262.3 mg of crude 3-(azetidin-3-yloxy)benzonitrile a1-45 as an oil. This oil is used in the next step without any further purification.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH3:32][C:33]([CH3:35])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:33]([CH3:35])[CH3:32])[CH2:6]2)[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH:27]([F:28])[F:29])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CC(C)=O
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (27 mg, 0.054 mmol), acetone (4.4 μL, 0.060 mmol), and triethylamine (23.5 μL, 0.169 mmol) in methylene chloride (0.4 mL) was added sodium triacetoxyborohydride resin (47 mg, 0.11 mmol). The resulting mixture was stirred for 2 h at room temperature. The mixture was filtered and concentrated and dried in vacuo to give 22 mg of the crude the product which will be used without purification. LCMS calculated for C22H28ClF2N6O (M+H)+: m/z=465.2; Found: 465.1.