Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[Cl:42][C:43]1[CH:44]=[C:45]([CH:53]=[CH:54][C:55]=1[Cl:56])CN1C=CC(N)=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:53]3[CH:45]=[CH:44][C:43]([Cl:42])=[C:55]([Cl:56])[CH:54]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(Cc2ccc(Cl)c(Cl)c2)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(Cl)c(Cl)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-(3,4-dichloro-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3,4-dichloro-benzyl)-1H-pyrazol-3-yl]-propionamide (133 mg, 79%) as a white solid: ESI-LRMS m/e calcd for C25H26Cl3N3O3S [M+] 553.1, found 554.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.22 (m, 2H, CH2), 1.42-1.90 (m, 8H, 4×CH2), 2.09-2.28 (m, 1H, CH), 3.24 (s, 3 H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 5.07 (s, 2H, NCH2), 6.71 (d, J=2.3 Hz, 1H, Ar), 6.95 (dd, Jo=8.2, Jm=2.0 Hz, 1H, Ar), 7.21 (d, Jm=2.0 Hz, 1H, Ar), 7.31 (d, J=2.3 Hz, 1H, Ar), 7.36 (d, Jo=8.2 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.14 (s, 1H, NH).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (85 mg, 0.28 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 150 μL, 0.29 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 68 mg, 0.28 mmol), 2,6-lutidine (66 μL, 0.56 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 57%) as a yellow oil: [α]25589=−9.4° (c=0.16, methanol); ES-HRMS m/e calcd for C26H36N3O3SiF3 (M+Na)+ 546.2370, observed 546.2367; 1H NMR (300 MHz, CDCl3) δ-0.06 (s, 6H, 2×SiCH3), 0.83 (s, 9H, 3×CH3), 1.57 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.57 (m, 1H, ArCHCO), 3.85 (t, J=5.3 Hz, 2H, OCH2), 4.05 (t, J=5.3 Hz, 2H, NCH2), 6.64 (d, J=2.2 Hz, 1H, Ar), 7.32 (d, J=2.2 Hz, 1H, Ar), 7.46-7.62 (m, 4H, Ar), 7.67 (brs, 1H, NH).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:28][N:27]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (230 mg, 1.73 mmol) described in Manufacturing Example 13-1-3 in anhydrous tetrahydrofuran (20 mL) was added (2-benzyloxy-pyridin-5-yl)-acetohydroximoyl chloride (1.00 g, 3.61 mmol) described in Manufacturing Example 12-1-5 under nitrogen atmosphere at room temperature. Triethylamine (965 μL, 6.92 mmol) was added dropwise to the mixture and stirred for 1.5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (470 mg, 73%).
Reaction SMILES: [CH2:1]([CH:9]1[O:11][CH:10]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:23][OH:24]>>[OH:11][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]([O:24][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CO
Reactant: CCCCCCCCC1OC1CCCCCCCC(=O)OC
Product: CCCCCCCCC(O)C(CCCCCCCC(=O)OC)OC

Procedure:
The methyl 8-(3-octyloxiran-2-yl)octanoate (2) (4.8 g; 0.015 mol), Amberlyst 15 (0.05 g) and methanol in excess (100 mL) were placed under reflux for 12 hours. The reaction mixture was filtered and the methanol removed using a rotary evaporator. The reaction mixture was dissolved in dichloromethane (100 mL) and washed with water (3×50 mL). The dichloromethane solution was separated and evaporated to obtain the intermediate compound 3.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)=O.[CH3:24][C@H:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1.C(O)(=O)C>C(Cl)Cl>[CH:21]1([C:19]([NH:18][C:16]2[CH:17]=[C:10]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][N:30]5[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:26][C@H:25]5[CH3:24])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][N:11]3[N:15]=2)=[O:20])[CH2:23][CH2:22]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1

Procedure:
N-(4-(4-Formylphenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (122 mg, 0.4 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (120 mg, 0.6 mmol) and (polystyrylmethyl)trimethylammonium cyanoborohydride (loading 4 mmol/g, 0.3 g, 1.2 mmol) were shaken in DCM (15 mL) and acetic acid (1.5 mL) at room temperature for 5 d. The beads were filtered off and the filtrate concentrated in vacuo to give (R)-tert-butyl 4-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-3-methylpiperazine-1-carboxylate which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a stirred solution of 2-bromo-1,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H2SO4 was added KNO3 by portions at 0° C. After this addition, the mixture was allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 78.1% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.91-7.87 (dd, 1H), 7.52-7.57 (dd, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1.[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[Br:5][C:6]1[CH:14]=[C:10]([C:11]([O:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Oc1ccccc1)c1cc(Br)ccc1O

Procedure:
80 ml of thionyl chloride was gradually added to a benzene suspension of 217 g of 5-bromosalicyclic acid and 113 g of phenol, followed by refluxing for ten hours under heating. After distilling off the benzene, ice-water was added to the residue, and the precipitate formed was collected by filtration, followed by drying. Yield: 210 g.
Reaction SMILES: C([O-])=O.[NH4+].C(O)=O.[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1)([O-])=O>CO.[Pd]>[NH2:8][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O=CO
Product: Nc1ccc2c(c1)C(=O)CCC2
Reaction time: 0.5 h

Procedure:
Ammonium formate (2 g), Pd/C (5%; 1 g), and formic acid (0.5 g; cat.) were added in that order to a solution of 7-nitro-1-tetralone (1.95 g; 10 mmol) in methanol (50 mL), and the mixture was stirred for 30 minutes. The solution was filtered, and the filtrate was concentrated. The remainder was soaked with methylene chloride (50+25 mL), and the mixture was filtered and concentrated. Yield 1.4 g (88%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:23])[CH2:19][C:20](O)=[O:21]>>[CH3:23][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:17])[CH2:19][C:20]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:21]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(C(F)(F)F)c2ccccc2c1=O)c1ccccc1

Procedure:
The product of Example 11B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58-11.60 (bs, 1H), 8.43 (dd, J=7.9, 1.3 Hz, 1H), 8.11-8.15 (m, 1H), 7.97-8.07 (m, 2H), 7.43-7.46 (m, 2H), 7.28-7.36 (m, 2H), 7.16-7.21 (m, 1H), 2.66 (s, 2H), 1.46 (s, 6H); MS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:33][CH3:34]>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH:8]([O:13][CH2:33][CH3:34])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12
Reactant: COC(=O)C(O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a cold solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate (0.100 g; 0.307 mmol) in dry DMF (1.5 ml) at −15° C. under nitrogen atmosphere was added LHMDS (1M in THF) (0.338 mL; 0.338 mmol) dropwise and the mixture was stirred at −15° C. for 15 min. Then, iodoethane (0.049 mL; 0.614 mmol) was added and the mixture was allowed to warm up to room temperature. After 72 h, the reaction was quenched by adding a saturated solution of ammonium chloride, extracted with dichloromethane and the combined organics were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-40%) in heptane furnished 0.040 g (37%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([O-])=[O:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.C1COCC1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[CH2:13][C:12]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])(=[O:11])[CH2:9][CH3:10]
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: CCC(=O)c1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1ccccc1NC(=O)CC(=O)OCc1ccccc1
Yield: 17.9 %

Procedure:
To a mixture of 1-(2-aminophenyl)propan-1-one (CAS1196-28-7) (4.6 g), monobenzyl malonate (7.2 g), and THF (46 mL) were added EDC.HCl (7.1 g) and HOBt.H2O (7.1 g), and the mixture was stirred at room temperature for 14 h and then heated to reflux for 8 h. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to obtain benzyl N-(2-propionylphenyl)malonamate (1.8 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1>>[CH3:22][O:21][C:16]1[CH:15]=[C:14]([Br:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COc1cc(Br)ccc1O
Reactant: BrCc1ccc2ccccc2c1
Product: COc1cc(Br)ccc1OCc1ccc2ccccc2c1
Yield: 62 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene was reacted with 4-bromo-2-methoxyphenol to give 3-methoxy-4-(naphth-2-ylmethoxy)bromobenzene (62%), m.p. 108° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].CN(C)C=O.Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:16]([F:21])[F:20]
Reactant: Oc1cc(Cl)ccc1Br
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cc(Cl)ccc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
The title compound was prepared according to the procedure disclosed in Published PCT Patent Application No. WO2011/003065 A2. To a solution of 2-bromo-5-chlorophenol (4.34 g, 20.92 mmol) (the oil from above) in N,N-dimethylformamide (21.8 mL, 20.9 mmol) was added sodium chlorodifluoroacetate (7.34 g, 48.1 mmol), cesium carbonate (9.54 g, 29.3 mmol), and water (2.18 mL, 20.9 mmol). The reaction was stirred at 100° C. for 16 h. The reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×70 mL). The organic layers were combined and washed with water (2×50 mL), 10% aq. citric acid (1×30 mL), brine, dried over MgSO4, filtered, and concentrated to afford 1-bromo-4-chloro-2-(difluoromethoxy)benzene (4.35 g, 16.9 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (dd, J=2.3, 8.6 Hz, 1H), 7.37 (t, J=73 Hz, 1H), 7.49 (dt, J=2.40, 0.81 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine (140 mg, 0.56 mmol), 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (144.37 mg, 0.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (214.42 mg, 1.12 mmol), and 1-hydroxybenzotriazole (HOBt) (120.91 mg, 0.89 mmol) were dissolved in dichloromethane (3 mL) at room temperature. Diisopropylethylamine (DIEA) (0.39 mL, 2.24 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (60 mL) and washed with water (1×20 mL) and brine (1×20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was then purified on Combiflash ISCO (0-30% Ethyl Acetate:Hexanes) to give the desired product (164 mg, 60% yield). 1H NMR (CDCl3) δ 8.52 (1H, t), 8.22 (1H, dt), 8.12 (1H, t), 8.03 (1H, dt), 7.85-7.81 (2H, m), 7.57 (1H, d), 7.35 (1H, s), 7.05-7.00 (2H, m), 3.80 (2H, d, J=4 Hz), 1.55 (6H, s); MS (ESI) m/z: Calculated for C23H18F4N4O2S: 490.11. found: 491.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: CCCc1ccc(C(=O)O)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1ccc(C(=O)Cl)c(F)c1

Procedure:
First, 1.1 g (6.1 mmol) of 2-fluoro-4-propylbenzoic acid was mixed with 1.1 g (9.1 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 80° C. for 2 hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude 2-fluoro-4-propylbenzoyl chloride.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:25][CH:26](O)[CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=3>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:25][CH:26]([F:7])[CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=3
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1cccc(NCC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
DAST [(Et2NSF3) 0.12 ml, 0.916 mmol] was added dropwise to a solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (0.102 g, 0.203 mmol) in 6.0 ml of anhydrous DCM at −78° C. The reaction was stirred at −78° C. for one hour before being slowly warmed to 0° C. over 5 hours. The reaction was quenched by addition of phosphate buffer (pH=8) and extracted with DCM. The aqueous phase was extracted twice with 10 ml DCM. The combined organics were dried over Na2SO4, filtered and concentrated. The crude reaction material was purified by flash chromatography on SiO2 (20% EtOAc/hexanes/0.2% TEA). Fractions containing the desired fluorinated product were further purified with 40% EtOAc/hexanes (+0.1% TEA). Isolated 5.7 mg desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[C:6]=4[CH:18]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: COc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (34 mg, 27%), MS (ISP) m/z=385.5 [(M+H)+], mp 143° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methoxy-phenyl)-1H-benzo[d]imidazole (intermediate N) (100 mg, 330 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (81.6 mg, 396 μmol).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[NH2:25][C@H:23]([CH3:24])[CH2:22][N:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H](C)N
Reaction time: 24 h
Yield: 53.7 %

Procedure:
In a 20 mL vial, to a solution of Example 59B (75 mg, 0.156 mmol) in MeOH (1 mL) was added a solution of hydrogen chloride (0.039 mL, 0.156 mmol) in dioxane and the mixture was stirred for 24 hr. The reaction was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 m particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to obtain the title compound (32 mg, 59%). 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.26 (d, J=6.78 Hz, 3 H) 1.40 (s, 9 H) 3.64-3.73 (m, 1 H) 3.86 (s, 3 H) 4.26-4.31 (m, 2 H) 7.09 (d, J=8.82 Hz, 1 H) 7.18 (s, 1 H) 7.41 (dd, J=8.82, 2.71 Hz, 1 H) 7.74 (d, J=2.71 Hz, 1 H); MS (DCI) m/z 382 (M+H)+.