Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:44]CC)([O:41]CC)([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C:22]3[N:23]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])[C:24](=[O:33])[C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:32])[N:12]=2)[CH:5]=1)=[O:2].C[Si](Br)(C)C>CC#N>[P:1]([OH:41])([OH:44])([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C:22]3[N:23]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])[C:24](=[O:33])[C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:32])[N:12]=2)[CH:5]=1)=[O:2]
Reactant: CCOP(=O)(OCC)Oc1cc(F)cc(-c2nn(Cc3cc4cccc(C)c4c(=O)n3-c3ccccc3C)c3ncnc(N)c23)c1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Cc1ccccc1-n1c(Cn2nc(-c3cc(F)cc(OP(=O)(O)O)c3)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
3-(4-Amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenyl diethyl phosphate 4302 (170 mg, 0.26 mmol) was dissolved in anhydrous CH3CN (5 mL) and cooled to 0° C. under an argon atmosphere. TMSBr (0.34 mL, 2.64 mmol) was slowly added via a syringe and the resulting mixture was stirred from 0° C. to RT for 16 h. LC-MS showed small amount of staRT ing material left, additional amount of TMSBr (0.1 mL) was added and stirred at RT for 5 h. LC-MS showed the complete conversion. The mixture was concentrated in vacuo, and the residue was dissolved in Et2O (10 mL) and H2O (0.5 mL) and stirred for 30 min. The mixture was concentrated in vacuo to affords the desired product, 3-(4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenyl dihydrogen phosphate 4303 (140 mg, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[S:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2c(Cl)ncnc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnc2c(CBr)csc12
Temperature: 100 °C

Procedure:
4-Chloro-7-methylthieno[3,2-d]pyrimidine (6.62 g, 33.0 mmol) and NBS (5.87 g, 33.0 mmol) were dissolved in CCl4 (100 mL) and benzoylperoxide (1.0 g, 80% purity) was added thereto. The reaction mixture was stirred at 100° C. for an hour, cooled to room temperature, filtered with Celite and concentrated to obtain the title compound having a yellow color without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[CH2:13]([O:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:14]1([CH2:13][O:20][CH2:21][CH:22]=[CH:23][CH2:24][O:10][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][C:2]([CH3:12])([CH3:1])[CH3:3])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: OC/C=C\COCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)OCC=CCOCc1ccccc1
Temperature: 0 °C

Procedure:
N-[(1,1-Dimethylethoxy)carbonyl]glycine (21.9 grams, 0.125 mol), cis-4-benzyloxy-2-buten-1-ol (25 mL, 0.15 mol), and 4-dimethylaminopyridine (1.5 grams, 0.013 mol) are dissolved in methylene chloride and stirred at 0° C. Then N,N-dicyclohexylcarbodiimide (31 grams, 0.15 mol) in 30 mL methylene chloride is added and the reaction is stirred at 0° C. for five minutes. The reaction is then stirred for an additional twelve hours at 25° C. Additional methylene chloride is added and the reaction is washed consecutively with 1 N HCl, sodium bicarbonate and then with brine. The organic extract is dried over magnesium sulfate and the solvent evaporated in vacuo to give an orange oil which is absorbed onto silica gel and applied to a dry silica column. The column is eluted with hexane/EtOAc (9:1) then with hexane/EtOAc (8:2) Product fractions are combined and dried in vacuo to give the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]1[NH:8][N:9]=[CH:10][C:6]=1[CH2:5]2.[Li]C1C=CC=CC=1.C1CCCCC1.C[CH2:28][O:29]CC.[Li]C(CC)C.C1CCCCC1.CN(C=O)C>C1COCC1>[NH:8]1[C:7]2[C:11]3[C:4]([CH2:5][C:6]=2[CH:10]=[N:9]1)=[CH:3][C:2]([CH:28]=[O:29])=[CH:13][CH:12]=3
Reactant: CCOCC
Reactant: Brc1ccc2c(c1)Cc1cn[nH]c1-2
Agent: [Li]C(C)CC
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)Cc1cn[nH]c1-2
Temperature: -78 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 6-bromo-1,4-dihydro-indeno[1,2-c]pyrazole (0.100 g, 0.425 mmol, see U.S. Pat. No. 6,297,238 for preparation) in THF (3 mL) at −78° C. was added PhLi in cyclohexane/ether (1.8 M, 0.71 mL, 1.28 mmol) followed by s-BuLi in cyclohexane (1.3 M, 0.98 mL, 1.28 mmol) 30 minutes later. The reaction mixture was stirred at −78° C. for 60 minutes and DMF (0.33 mL, 4.25 mmol) was added. The dry ice bath was removed after 30 minutes. After an additional 30 minutes, the reaction was quenched with water. The reaction mixture was extracted with EtOAc, washed with 50% brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography eluted with EtOAc/hexane (7:3 to 8:2) to give 0.053 g (68%) of the desired product as brown solid. MS (DCI/NH3) m/z: 185.0 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 3.76 (s, 2H), 7.63 (s, 1H), 7.62-7.97 (m, 2H), 8.04 (s, 1H), 10.00 (s, 1H).
Reaction SMILES: C(O)(=O)C.[CH:5]1([O:11][N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15](=O)[CH2:14][C:13]2([CH3:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:23]([NH2:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>O1CCCC1>[CH:5]1([O:11][N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([NH:35][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:14][C:13]2([CH3:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: CCCCCCCCCCCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 21 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
Acetic acid (22.0 g, 367 mmol) is added dropwise to a solution of 15.0 g (59.2 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one and 54.9 g (296 mmol) of dodecylamine in 200 ml of dry tetrahydrofuran containing 5A molecular sieves (25 g). The reaction mixture warms during the addition. The mixture is then diluted with tetrahydrofuran (150 ml) and cooled to 21° C. Sodium cyanoborohydride (4.46 g, 7.1 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 4 hours, then filtered. The filtrate is concentrated and the residue is partitioned between ether (400 ml) and 5% sodium hydroxide (250 ml). The organic layer is dried over magnesium sulfate, filtered, and concentrated. Residual dodecylamine is removed by Kugelrohr distillation (110° C., 0.3 mm). The crude product is purified by chromatography (silica gel) to afford 20.4 g (82% yield) of the title compound, as a nearly colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:51])([CH2:48][CH:49]=[CH2:50])[CH2:3][O:4][C:5]([NH:7][C@@H:8]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH2:47])[C:9]([N:11]1[CH2:19][C@H:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:31]=[CH2:32])[CH:29]=3)[N:24]=[C:23]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:22]=2)[CH2:17][C@H:12]1[C:13]([O:15]C)=[O:14])=[O:10])=[O:6].Cl>C1COCC1.CO.[Li+].[OH-]>[CH3:1][C:2]([CH3:51])([CH2:48][CH:49]=[CH2:50])[CH2:3][O:4][C:5]([NH:7][C@@H:8]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH2:47])[C:9]([N:11]1[CH2:19][C@H:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:31]=[CH2:32])[CH:29]=3)[N:24]=[C:23]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:22]=2)[CH2:17][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])=[O:6]
Reactant: C=CCCCCC[C@H](NC(=O)OCC(C)(C)CC=C)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCCC[C@H](NC(=O)OCC(C)(C)CC=C)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)O
Yield: 89.4 %

Procedure:
A solution of the product from Step 1 (962 mg, 1.38 mmol) in THF (10 mL), MeOH (1 mL) and 1 M aqueous LiOH (9.65 mL) was stirred at RT for 2 hours. The reaction solution was acidified to pH 5 with 1 M aqueous HCl and extracted with EtOAc (3×100 mL). The combined EtOAc layers were washed with water (50 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title product (844 mg). LRMS (ESI) m/z 684.5 [(M+H)+; calcd for C40H50N3O7: 684.4].
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:34]4[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=4)[CH:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[OH:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:34]4[CH:35]=[CH:36][C:37]([S:40][CH3:41])=[CH:38][CH:39]=4)[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:3])=[O:4]
Reactant: CSc1ccc(C(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)C(O)c2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1ccc(C(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)C(=O)c2ccccc2)cc1
Temperature: 21 °C
Reaction time: 2 h

Procedure:
To a solution of the crude oil from Step 3 in CH2Cl2 (5 mL) at 21° C. was added Dess-Martin periodinane (255 mg, 0.6 mmol) portionwise. The resulting reaction mixture was stirred 2 h at 21° C., then diluted with a sodium bicarbonate solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 50:50) provided the 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-1-phenyl-propan-1-one compound as a white foam.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:11]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:12]=2[CH2:13][N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)([O:9][CH3:10])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:45](F)(F)C1C=CC(C#N)=CC=1.C1([Mg]Br)CCCCCC1.C[Mg]Br.CI>>[CH:6]1([C:7]([C:11]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][C:12]=2[CH2:13][N:14]([CH2:21][C:22]2[CH:23]=[C:24]([C:32]([F:33])([F:35])[F:34])[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)([O:9][CH3:10])[CH3:8])[CH2:45][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(C)(CC1CCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: Br[Mg]C1CCCCCC1
Agent: C[Mg]Br
Solvent: CI
Product: COC(C)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCCC1

Procedure:
This compound was prepared by an analogous series of reactions to that used for the preparation of N-(2-(1-cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine from 2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrile by the addition of cycloheptylmagnesium bromide followed by methylmagnesium bromide then alkylation with methyl iodide LC-MS calc 637.5, found 606 (M-OCH3).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1.[Cl-].[NH4+].O1CCCC1.CO>O>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1
Reactant: COCc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(N)c(N)cc1C(=O)OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a mixed liquid of 4.70 g of methyl 4-amino-2-(methoxymethyl)-5-nitrobenzoate, 750 mg of ammonium chloride, 47.0 mL of tetrahydrofuran, 94.0 mL of methanol, and 14.0 mL of water was added 7.65 g of reduced iron, followed by stirring at 80° C. overnight. After cooling to room temperature, the insoluble materials were filtered through celite and the filtrate was evaporated under reduced pressure to obtain 4.33 g of methyl 4,5-diamino-2-(methoxymethyl)benzoate as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH:18](O)([CH3:20])[CH3:19]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH:18]([CH3:20])[CH3:19])=[O:11]
Reactant: Cc1ccc(I)c(CC(=O)O)c1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: Cc1ccc(I)c(CC(=O)OC(C)C)c1

Procedure:
2-Iodo-5-methylphenylacetic acid (20.0 g, 72 mmol) and a catalytic amount of 98% sulfuric acid (0.2 ml) are dissolved in isopropyl alcohol (200 ml) and heated to reflux temperature for 48 hours. The solvent is removed on a rotovap and the residual oil partitioned between EtOAc (500 ml) and saturated NaHCO3 solution (500 ml). The organic layer is separated, dried (MgSO4) and concentrated on a rotovap. The residual oil is distilled using a kugelrohr apparatus to give a clear, colorless oil which solidifies on standing at room temperature to give isopropyl 2-iodo-5-methylphenylacetate, m.p. 48-50°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC(CC(=O)OCC)Cc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)Cc1cccc(OC)c1
Yield: 99 %

Procedure:
Ethyl ester 91 (3.12 g, 11.8 mmol) was saponified with 1 N NaOH in THF and EtOH to give 2.76 g (99%) of the title compound (92) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.87 (t, J=6.8 Hz, 3H), 1.25-1.45 (m, 4H), 2.10-2.22 (m, 1H), 2.25-2.30 (m, 2H), 2.50-2.60 (m, 1H), 2.65-2.75 (m, 1H), 3.79 (s, 3H), 6.70-6.80 (m, 3H), 7.19 (d, J=7.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[C:38]([CH3:44])=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=1>>[CH3:44][C:38]1[C:37]([C:20]2[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:22][CH:21]=2)=[CH:42][CH:41]=[C:40]([CH3:43])[N:39]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1ccc(Br)c(C)n1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c(C)n1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-bromo-2,6-dimethylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.012, m/z=463.1; 1H NMR (CDCl3) 1.32 (m, 2H), 1.49 (d, 3H), 1.62 (m, 2H), 1.86-1.96 (m, 2H), 2.17-2.29 (m, 3H), 2.31 (s, 3H), 2.49 (s, 3H), 2.93 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.88-7.03 (m, 7H), 7.25 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13](Br)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1.[NH:19]1[C:23](B(O)O)=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:23]3[NH:19][N:20]=[CH:21][CH:22]=3)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (5.0 g, 15.0 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added 1H-pyrazole-5-boronic acid (1.70 g, 15.0 mmol), Pd(PPh3)4 (1.75 g, 1.52 mmol), and potassium carbonate (6.3 g, 45.6 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (ethyl acetate:hexane, 50:50) to provide 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid 4-fluoro-benzylamide as yellow solid (3.25 g 68%) MS (M+H)+=317; Rt=1.13 min; HRMS (M+H)+=317.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]1[C:21]([F:28])=[C:22]([NH2:27])[C:23]([F:26])=[CH:24][CH:25]=1)[CH3:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH:1]1([NH:6][C:7]2[C:12]([CH:13]=[N:27][C:22]3[C:23]([F:26])=[CH:24][CH:25]=[C:20]([O:19][CH2:17][CH3:18])[C:21]=3[F:28])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1ccc(F)c(N)c1F
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CCOc1ccc(F)c(N=Cc2cnc(SC)nc2NC2CCCC2)c1F
Reaction time: 48 h
Yield: 82 %

Procedure:
To a solution of the 8.22 g (34.7 mmol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 170 mL of toluene was added 6.00 g 34.7 mmol, 1 equivalent) of 3-ethoxy-2,6-difluoro-phenylamine and 2.01 g (8.66 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting emulsion was filtered through fiberglass filter paper. The methylene chloride layer was isolated from the filtrate, then washed first with a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material on a Biotage 500 g silica gel column with 4:1 hexane/ethyl acetate gave 11.1 g (82%) of the title compound as a solid: mp 136° C.–141° C. MS (APCI) (m+1)/z 393.2 Analysis calculated for C19H22F2N4SO: C, 58.15; H, 5.65; N, 14.28. Found: C, 58.22; H, 5.68; N, 14.26.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].C([O-])([O-])=O.[K+].[K+].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:26])([F:38])[F:39])[CH:30]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1cccc(OC(F)(F)F)c1
Temperature: 90 °C
Yield: 43.8 %

Procedure:
A mixture of 4-bromo-6-chloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (150 mg, 0.44 mmol), K2CO3 (183 mg, 1.31 mmol) and 3-trifluoromethoxyphenylboronic acid (61 mg, 0.35 mmol) in dimethyl formamide (4 ml) in a sealed tube was purged with argon for 20 min followed by addition of Pd(PPh3)4 (51 mg, 0.04 mmol), again purged with argon for 10 min and the reaction mixture was heated at 90° C. for 5 h under stirring. After cooling, the reaction mixture was filtered through celite bed and washed with ethyl acetate. The organic phase was concentrated in vacuo and then partitioned between water and ethyl acetate. The organic phase was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a crude residue. This crude residue was purified by flash column chromatography (100-200 mesh silica, eluting with 2% EtOAc in hexane) to afford pure 6-chloro-2-isopropyl-4-(3-trifluoromethoxy-phenyl)-quinoline-3-carboxylic acid methyl ester (65 mg, 35%) as pale yellow sticky liquid. LC-MS: 424 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([NH2:22])[CH:21]=[C:15]2[CH2:14]1>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:22][C:20]2[CH:21]=[C:15]3[CH2:14][N:13]([CH3:12])[CH2:18][CH2:17][N:16]3[N:19]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CN1CCn2nc(N)cc2C1
Product: CN1CCn2nc(Nc3cc(Cl)nn4ccnc34)cc2C1

Procedure:
Following the procedures as described in Example 104b, and starting with 8-bromo-6-chloroimidazo[1,2-b]pyridazine 104a, 1.43 g, 6.2 mmol) and 124e (900 mg, 5.9 mmol) afforded 124f was as a yellow solid (800 mg, 44%). MS-ESI: [M+H]+ 304.1
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12](=O)(=O)[C:11]=2[CH:29]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:30]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12][C:11]=2[CH:29]=1)[CH3:31]
Reactant: CCN(CC)CCOc1ccc2c(c1)S(=O)(=O)c1cc(OCCN(CC)CC)ccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(c1)sc1cc(OCCN(CC)CC)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a 0° C. mixture of 3,7-bis(2-diethylaminoethoxy)dibenzothiophene-5,5-dioxide (5.30 g, 1.2 mmol; see J. Med. Chem., 1978, 21, 1084) in dry THF (10 mL) was added portion-wise lithium aluminum hydride (90 mg, 2.4 mmol, Aldrich). The reaction mixture was allowed to warm to ambient temperature and then heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was quenched by sequential addition of H2O-THF (1:9, 1 mL), aq. NaOH (2.5 N, 0.1 mL), and H2O (0.3 mL). The mixture was stirred for 30 minutes, filtered, and the residue was purified by flash chromatography (35 g silica gel, eluting with 4-8% of 10% NH4OH/MeOH in CH2Cl2) to afford the title compound (250 mg, 51% yield).