Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH:3]([CH3:5])[CH3:4].C1COCC1.Br[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[Cl:24]>>[Cl:24][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:13]=1[CH2:2][CH:3]([CH3:5])[CH3:4])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC(C)C[Zn+]
Reactant: CCOC(=O)c1ccc(Br)c(Cl)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(C)C)c(Cl)c1

Procedure:
A solution of isobutylzinc bromide in THF (0.5 M, 30 mL, 15.0 mmol) was added under argon to ethyl 4-bromo-3-chlorobenzoate (D16) (2.00 g, 7.60 mmol) and then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (930 mg, 1.14 mmol) was added. The reaction was heated to reflux for 4.5 h. The mixture concentrated in vacuo and the residue partitioned between ethyl acetate (125 mL) and water (125 mL). A solid formed, which was filtered off and discarded. The organic layer was washed with water (100 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by silica chromatography, eluting with 0-5% EtOAc in hexane over 30 minutes to give the title compound as a colourless oil (1.76 g, 7.33 mmol). δH (d6-DMSO, 400 MHz): 7.91 (1H, d), 7.80 (1H, dd), 7.46 (1H, d), 4.30 (2H, q), 2.66 (2H, d), 1.88-2.01 (1H, m), 1.32 (3H, t), 0.89 (6H, d).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1.[OH-].[Na+]>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCc3ccco3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccco3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 60 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(furan-2-ylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (31 mg, 0.050 mmol) in 1,4-dioxane (2 mL) was added 1N NaOH (0.248 mL, 0.248 mmol). The mixture was heated to 85° C. for 22 h then was cooled to rt. The crude product was purified by prep HPLC. The fractions containing the expected product were combined and were concentrated under reduced pressure to afford the title compound (19.3 mg, 0.030 mmol, 60.5% yield) as a clear film. LCMS: m/e 610.69 (M+H)+, 2.35 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 8.00 (d, J=7.78 Hz, 2H), 7.37 (d, J=1.00 Hz, 1H), 7.23 (d, J=7.78 Hz, 2H), 6.33 (dd, J=3.14, 1.88 Hz, 1H), 6.21 (d, J=2.76 Hz, 1H), 5.53 (br. s., 1H), 5.29-5.34 (m, 1H), 4.72 (d, J=1.76 Hz, 1H), 4.60 (s, 1H), 3.67 (s, 2H), 2.64 (td, J=10.85, 5.40 Hz, 1H), 1.71 (s, 3H), 1.10-1.15 (m, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.97-2.18 (m, 22H), 0.96 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34]C)=[CH:23][N:22]=3)[C:5]=2[CH3:36])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN1CCCC1=O>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([OH:34])=[CH:23][N:22]=3)[C:5]=2[CH3:36])[CH2:3][CH2:2]1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
310 mg of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 2-1-12 (0.629 mmol, 1 eq.) were dissolved in 27.2 mL of dry 1-methylpyrrolidin-2-one. 348 mg of potassium carbonate (2.52 mmol, 4.0 eq.), molecular sieve and 97 μL benzenethiol (0.944 mmol, 1.5 eq.) were added. The mixture was stirred for 1 hour at 150° C. bath temperature. 348 mg of potassium carbonate (2.52 mmol, 4.0 eq.) and 97 μL benzenethiol (0.944 mmol, 1.5 eq.) were added again and the mixture was stirred for a further hour at 150° C. bath temperature. Then the reaction mixture was partitioned between aqueous half saturated ammonium chloride solution and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over a silicone filter and concentrated in vacuo. The purification of the residue by flash chromatography provided 191 mg (0.36 mmol, 56%) of analytically pure target compound.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]#[CH:36]>>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]#[C:36][C:13]1[CH:12]=[C:11]2[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:10]2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1Cl
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3Cl)ccc12

Procedure:
7-(2-chlorophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 10% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 2-chlorophenylacetylene. The title compound was isolated as an orange solid and as a 80/20 mixture of Z/E oxime isomers.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]2=[O:18])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.CC(C)([O-])C.[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][N:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][CH2:12][CH2:13][CH:6]([N:5]2[C:4](=[O:19])[C:3]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]3[C:1]2=[O:24])[C:7]1=[O:18])=[O:34])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2CCCC1N1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one (1.7 g) in dimethylformamide (10 ml) is stirred at 0° C. under a nitrogen atmosphere. A solution of potassium t-butoxide (0.75 g) in dimethylformamide (6 ml) is added and the reaction mixture is stirred at 0° C. for five minutes. A solution of ethyl bromoacetate (1.0 g) in dimethylformamide (5 ml) is added and the reaction mixture stirred at 0° C. for 11/2 hours. Water (3 ml) is added, and the reaction mixture is evaporated under high vacuum. The residue is distributed between ethyl acetate (100 ml) and water (50 ml) and the aqueous layer is washed with water (50 ml) and dried over sodium sulfate. The residue is recrystallized from methanol/ether to give 1-ethoxycarbonylmethyl-3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one, mp 79°-81° C. used in the next synthetic step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.3 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indole (D16) (580 mg, 2.71 mmol) in dichloromethane (20 mL) was added {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (1.33 g, 5.42 mmol), copper (II) acetate (984 mg, 5.42 mmol), triethylamine (0.755 mL, 5.42 mmol) and powdered 4A molecular sieves (2 g, 2.71 mmol). The mixture was stirred at room temperature in the presence of air for 3 days. The reaction was filtered through a pad of celite and washed with dichloromethane. The organic solution was washed with water and then the aqueous phase re-extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The product was partially purified by silica gel chromatography eluting with 5-20% ethyl acetate in hexane to yield the title compound (D17), (980 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][C:12]=1[C:27](OCC)=[O:28]>C1C=CC=CC=1>[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:13][C:12]=1[C:27]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:28]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1O
Reactant: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(Nc1ccccn1)c1nc(-c2ccccc2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a stirred slurry of 1.14 g of sodium hydride (as a 50% oil dispersion) in 100 ml of benzene was added 2.25 g of 2-aminopyridine. After stirring at room temperature for 15 minutes the slurry was treated with a solution of 2.25 g of 4-hydroxy-1-phenyl-3-isoquinolinecarboxylic acid, ethyl ester in 50 ml of benzene. After refluxing for one hour, the reaction mixture was cooled to room temperature, quenched with water, and extracted with three 100 ml aliquots of hot tetrahydrofuran. The organic layer was dried over magnesium sulfate, filtered, and evaporated to yield 1.7 g (65%) of 4-hydroxy-1-phenyl-N-(2-pyridyl)-3-isoquinolinecarboxamide. Recrystallization from dichloromethane afforded the analytical sample, m.p. 228°-230° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][CH2:43][NH:44][CH:45]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[O:50]=[S:47]1(=[O:51])[CH2:48][CH2:49][CH:45]([NH:44][CH2:43][CH2:42][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:46]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S1(=O)CCC(NCCCl)C1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 62.9 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.092 mmol), 3-((2-chloroethyl)amino)tetrahydrothiophene 1,1-dioxide (45.4 mg, 0.230 mmol), potassium phosphate (58.5 mg, 0.276 mmol) and potassium iodide (30.5 mg, 0.184 mmol) in acetonitrile (1 mL) was heated up at 120° C. for 18 hours. The reaction mixture was quenched with distilled water (3 mL), extracted with dichloromethane (3×3 mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product as a white solid (40 mg, 62%). LCMS: m/e 705.48 (M+H)+, 2.44 min (method 11).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[N:11](S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(=[O:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)ncc1N(S(=O)(=O)c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ncc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 84 %

Procedure:
To a solution of N-(4-acetyl-6-chloropyridin-3-yl)-4-nitro-N-(4-nitrophenylsulfonyl)benzenesulfonamide (1.0 equiv.) in 2:1 THF/MeOH (0.05 M) was added 1 M LiOH (aq.) (3.1 equiv). The resulting purple solution was stirred at rt for 15 hours, at which time 1 M HCl (3.1 equiv) was added. The volatiles were removed in vacuo and ethyl acetate (700 mL) and H2O (200 mL) were added. Upon separating the organic was washed with NaHCO3(sat.) (200 mL), with NaCl(sat.) (200 mL), dried over MgSO4, filtered and concentrated. Purification by column chromatography (50% ethyl acetate/hexanes with 0.1% AcOH, Rf=0.6) yielded N-(4-acetyl-6-chloropyridin-3-yl)-4-nitrobenzenesulfonamide (84%). LCMS (m/z): 356.0 (MH+); LC Rt=3.81 min. 1H NMR (CDCl3): δ 8.89 (s, 1H), 8.32 (m, 2H), 8.06 (m, 2H), 7.62 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH:36]1([NH:39][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]([C:13]([CH3:15])([CH3:16])[CH3:14])=[N:10][C:9]=3[C:17]3[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]4[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=4[F:33])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[CH:5]=[CH:4][N:3]=2)[CH2:38][CH2:37]1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: NC1CC1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NC3CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 290 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.464 mmol) and cyclopropylamine (0.163 mL, 2.31 mmol), the title compound was obtained as a white solid (40 mg, 14%). MS (ESI): 560 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([Cl:28])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Compound 37 (1 g, 3 mmol) was mixed with thionyl chloride (7.2 g, 60 mmol) and 3 drops of DMF. The reaction mixture was refluxed for 3 h under nitrogen. After cooling down to room temperature, thionyl chloride was removed under reduced pressure. Toluene (5 mL) was then added, and the mixture was dried under reduced pressure again. This process was repeated twice to ensure all the excess of thionyl chloride was removed. The compound 38 was further dried under high vacuum for half an hour and was used directly in the next step without purification.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (0.55 g, 1.09 mmol) in DCM (4 mL) is treated with TFA (2 mL) and stirred at RT. After 2 hours, the solvent is removed in vacuo to yield the title compound which is used in the next step without further purification. MS (ES+) m/e 304 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>CC(N(C)C)=O.O>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:17]1[CH:18]=[CH:13][C:14]([C:23]([F:26])([F:24])[F:25])=[CH:15][C:16]=1[C:19]([F:20])([F:21])[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCCOc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h

Procedure:
(2-Hydroxy-ethyl)-carbamic acid tert-butyl ester (0.2 mL, 1.29 mmol) is dissolved in 3 mL dry dimethyl-acetamide. 2-Potassium-1,1,1,3,3,3-hexamethyl-disilazane (0.52 g, 2.6 mmol, 2 equiv.) is added, followed by 1-bromo-2,4-bis-trifluoromethyl-benzene 31 (0.26 mL, 1.5 mmol, 1.2 equiv.). The mixture is stirred at 60° C. under nitrogen for 18 hours. The mixture is cooled, diluted with 50 mL water and extracted with dichloromethane (3×50 mL). The combined organic extracts are washed with water and 10% aqueous citric acid, dried over Na2SO4 and concentration. Silica gel chromatography (5% to 25% ethyl acetate in hexanes) yielded [2-(2,4-Bis-trifluoromethyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester 32 as a colorless, mobile oil: 1H-NMR (400 MHz, CDCl3) δ=7.61 (s, 1H), 7.00 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 5.10 (s, 1H), 4.26 (t, J=4 Hz, 2H), 3.65 (m, 2H), 1.45 (s, 9H). 19F-NMR (376 MHz, CDCl3) δ=−61.5, −62.0. No molecular ion could be obtained; a loss of tert-butyl group is observed: MS calculated for C11H10F6NO3 (M+H+—C4H8) 318.1, found 318.3.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[C:31]([N+:32]([O-:34])=[O:33])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1[N+](=O)[O-]

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 66.1.1) to give the title compound as a white solid. (HPLC: tR 2.62 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.72-8.66 (m, 1H), 8.46-8.39 (m, 1H), 8.18-8.10 (m, 2H), 8.05-7.96 (m, 1H), 7.58-7.53 (m, 1H), 4.07 (s, 3H), 3.91 (s, 3H), 3.59 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [CH3:1][C@@:2]([C:11](O)=[O:12])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].[BH4-].[Na+].II>C1COCC1>[NH2:3][C:2]([CH3:1])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][OH:12]
Reactant: C[C@](N)(Cc1ccccc1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)(CO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-α-methyl-phenylalanine (1.74 g, 9.71 mmol) in 30 mL THF at rt was added NaBH4 (0.92 g 24.27 mmol) in one portion. The solution was cooled to 0° C. Iodine (2.46 g, 9.71 mmol) in 5 mL THF was added dropwise over 30 min. After the addition was complete, the reaction was heated to reflux for 2 days. The reaction was then cooled to 0° C. and quenched by the addition of methanol until the bubbling subsided. The reaction mixture was acidified by the addition of 6N HCl until pH 1, stirred at 50° C. for 30 min and concentrated in vacuo. Purification using ion exchange chromatography (SCX cartridge) afforded 2-amino-2-methyl-3-phenylpropan-1-ol I as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.18 (m, 5H), 3.36 (A of AB, d, J=10.4 Hz, 1H), 3.31 (B of AB, d, J=10.4 Hz, 1H), 2.70 (s, 2H), 1.04 (s, 3H).
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[F:1][C@H:2]1[C@H:6]([O:7][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](F)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 0 °C

Procedure:
(trans)-Benzyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (2.0 g, 8.36 mmol) was added to dichloromethane and cooled to 0° C. Methanesulfonyl chloride (1.30 mL, 16.7 mmol) and triethylamine (2.3 mL, 16.7 mmol) were sequentially added, and the reaction was allowed to warm to ambient temperature overnight under vigorous stirring. The following day, additional dichloromethane was added, and the reaction mixture was washed with a saturated solution of NaHCO3. The combined organic layers were dried over MgSO4, filtered and evaporated. The crude oil was purified on silica gel using ethyl acetate and hexane to produce 2.0 g (70% isolated yield) of the desired product as an oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2ccccc2F)C1
Agent: B
Solvent: C1CCOC1
Product: Fc1ccccc1[C@H]1CCCN(C[C@H]2COc3ccccc3O2)C1
Yield: 235.6 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(2-fluorophenyl)piperidin-1-yl]methanone (10 mg, 0.0035 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 2.7 mg of the title compound.