Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Li]CCCC.N1([CH:25]=[O:26])CCCCC1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH:25]=[O:26])[CH:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1cc(-c2ccccc2)ccn1
Reactant: O=CN1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)ccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-bromo-4-phenylpyridine (500 mg; 2.13 mmol) in anh. THF (9 ml) was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.33 ml; 2.13 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 1 h. Commercially available piperidine-1-carbaldehyde (483 mg; 4.27 mmol) was added dropwise to the cooled (−78° C.) reaction mixture, and stirring was continued at −78° C. for 15 min., and then at 0° C. for 1 h. Aq. sat. NH4Cl (25 ml) and AcOEt (50 ml) were added, and the separated organic layer was further washed with brine (20 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (toluene/AcOEt=7/3) afforded 4-phenylpicolinaldehyde as a yellow solid. LC-MS (conditions A): tR=0.43 min.; [M+H]+: 184.48 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](CC)(CC)CC)=[CH:4][C:3]=1[C@:17]1([CH2:28][F:29])[CH2:22][C@@H:21]([C:23]([F:26])([F:25])[F:24])[O:20][C:19]([NH2:27])=[N:18]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:17]2([CH2:28][F:29])[CH2:22][C@@H:21]([C:23]([F:24])([F:25])[F:26])[O:20][C:19]([NH2:27])=[N:18]2)[CH:4]=1)#[CH:9]
Reactant: CC[Si](C#Cc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Yield: 96 %

Procedure:
A solution of (4S,6S)-4-(2-fluoro-5-((triethylsilyl)ethynyl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.285 g, 2.97 mmol from above) in 20 mL of THF was treated with tetrabutylammonium fluoride (1.0 M in THF) (3.27 mL, 3.27 mmol) at rt for 45 min. The solvent was removed under vacuum and the residue was dissolved in 2 mL of DCM and purified using the Shoko instrument with 40 g pre-packed silica gel column and EtOAc in hexanes as eluent (0-50% 20 min, 50% 10 min). Desired fractions were combined and concentrated to dryness to give the titled compound as a slightly colored oil: 0.905 g, 96% yield. MS m/z=319.0 [M+H]+. Calculated for C14H11F5N2O: 318.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Product: O=C(C[C@@H]1CCCN1C(=O)OCc1ccccc1)OCC(=O)c1ccccc1
Yield: 48.3 %

Procedure:
The title compound (0.700 g) was prepared from (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid benzyl ester (1.00 g, Aoyama et al, Chem. Pharm. Bull., 3249, 29,11, 1981) and 2-bromoacetophenone (0.760 g) according to the method of description 36.
Reaction SMILES: [CH3:1][N:2]([C@H:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23])[S:3]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[CH:7]=1)(=[O:5])=[O:4].[Li]N([Si](C)(C)C)[Si](C)(C)C.Br[CH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][N:40]=[C:39]2[Cl:46]>C1COCC1>[Cl:46][C:39]1[C:38]2[C:43](=[CH:44][CH:45]=[C:36]([CH2:35][N:20]3[CH2:21][CH2:22][C@H:18]([N:2]([CH3:1])[S:3]([C:6]4[CH:15]=[CH:14][C:13]5[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=5)[CH:7]=4)(=[O:5])=[O:4])[C:19]3=[O:23])[CH:37]=2)[N:42]=[CH:41][N:40]=1
Reactant: Clc1ncnc2ccc(CBr)cc12
Reactant: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCNC3=O)cc2c1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc5ncnc(Cl)c5c4)C3=O)cc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 52.1 %

Procedure:
To a solution of 7-methoxynaphthalene-2-sulfonic acid methyl-(2-oxopyrrolidin-3-(S)-yl)-amide (0.35 g, 1.04 mmol) in THF (7 mL) at 0° C. is added LiN(SiMe3)2 (1 mL, 1 mmol, 1 M solution in THF). The solution is stirred at 0° C. for 40 minutes. After this time, 6-bromomethyl-4-chloro-quinazoline (0.24 g, 0.94 mmol) is added. The resulting solution is stirred for 4 hours. The reaction is quenched by the addition of a saturated NH4Cl solution. The solution is diluted with EtOAc and water. The layers are separated. The organic layer is washed with water and brine. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 40% EtOAc/CH2Cl2 to give the title compound (0.25 g, 0.49 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[CH:13](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]=[CH:13][NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cccc2[nH]cnc12
Temperature: 90 °C

Procedure:
Ester 2 (1.7 g, 10.2 mmol), triethyl orthoformate (2.5 mL) and p-toluenesulfonic acid (10 mg) were mixed in “Performance Fluid” (3M Co., 40 mL) and refluxed with reversed Dean-Stark trap at 90° C. for 3 h. The reaction mixture was cooled to room temperature and the solid formed was filtered, washed with hexanes and dried to give 1.65 g (92%) of pure 3: 1H NMR (DMSO-d6) δ 12.59 (br.s, 1H), 8.32 (s, 1H), 7.97 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=6.5 Hz), 7.32 (t1, 1H, J=8.0 Hz), 3.95 (s, 3H).
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.C([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:29])=[CH:24][CH:23]=2)[C:20]=1[CH3:21])=O)C.[OH-].[Li+].[Li].[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CO.CN(C)C=O.O>[CH3:21][C:20]1[N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[O:29])=[CH:24][CH:23]=2)[N:18]=[CH:17][C:16]=1[C:14]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:13]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C(=O)N2CCCC2)cnn1-c1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1
Reaction time: 18 h

Procedure:
5-Methyl-1-[4-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester from Example 56 (270 mg, 0.66 mmole) is hydrolysed using lithium hydroxide in aqueous methanol and the resulting lithium salt recovered by freeze drying. The lithium salt, pyrrolidine (140 mg, 2 mmole), TBTU (325 mg, 1 mmole) and triethylamine (212 mg, 2 mmole) are dissolved in dimethylformamide (10 mL) and the mixture is stirred for 18 hours. The reaction is diluted with water, extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The product is purified by chromatography on silica gel using 10% methanol in dichloromethane and the title compound recovered by crystallization from ethyl acetate. MS (m/e): 436.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[C:19]([O:27][CH3:28])[CH:18]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1cc(O)ccc1CC(=O)O
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1CC(=O)O
Yield: 87 %

Procedure:
Using an analogous procedure to that described in the portion of Note [1] below Example 8 that is concerned with the preparation of starting materials, 4-chloro-6,7-dimethoxyquinazoline was reacted with 2-(4-hydroxy-2-methoxyphenyl)acetic acid to give 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)-2-methoxyphenyl]acetic acid in 87% yield; 1H NMR: (DMSOd6) 3.55 (s, 2H), 3.75 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.83 (d, 1H), 6.97 (s, 1H), 7.27 (d, 1H), 7.39 (s, 1H), 7.55 (s, 1H), 8.57 (s, 1H); Mass Spectrum: M+H+ 371.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH2:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1>[Pd].CO>[C:3]1([CH2:9][C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1cccc(Cl)c1Cc1nnn[nH]1
Agent: [Pd]
Solvent: CO
Product: c1ccc(Cc2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 5-(2,6-dichlorophenylmethyl)tetrazole (355 mg), 5% palladium on activated carbon (93 mg) and methanol (8 ml) was stirred for 1 h room temperature under an atmosphere of hydrogen gas. The reaction mixture was filtered through Celite (trade mark) and the filtrate was concentrated to give the title compound having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:27][O:26]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CO2)cc1
Reactant: C1CCNCC1
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC(O)CN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 11.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4-carboxamide (0.025 g, 0.0671 mmol) in MeOH (1 ml) was added piperidine (0.017 g, 0.201 mmol). The reaction was heated to 100° C. via microwave irradiation and held at this temperature for 15 minutes. The crude reaction was then purified by preparative HPLC to give 2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)oxazole-4-carboxamide (0.0036 g, 0.0079 mmol, 12%) as an off white powder. 1H NMR (DMSO) δ 1.34-1.41 (2H, m), 1.46-1.54 (4H, m), 2.35-2.48 (6H, m), 3.92-4.01 (2H, m), 4.04-4.08 (1H, m), 7.08-7.12 (2H, m), 7.34-7.41 (2H, m), 7.66 (1H, br. s), 7.68 (1H, br, s), 7.69-7.76 (1H, m), 8.20-8.24 (2H, m). LCMS (2) 3.06 min; m/z (ES+) 458.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[CH:4][CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:17]1[C:13]([C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:15]=[CH:16][C:2]([NH2:1])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[N:14][N:19]=[N:18]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Oc2ccc(N)cc2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1
Temperature: 70 °C

Procedure:
A mixture of 4-(4-amino-phenoxy)-pyridine-2-carbonitrile (Example 102) (2.6 g, 12.3 mmol), sodium azide (6.6 g, 102 mmol, 8.3 equiv), and ammonium chloride in DMF abs. (180 mL) is heated to 70° C. for 7.5 h, under an argon atmosphere. The reaction mixture is allowed to cool to rt, filtered through a glass sintered funnel and concentrated in vacuo. The residue is purified by silica gel (390 g) column chromatography (CH2Cl2/MeOH, 80/20) to afford the title compound as a beige solid: ES-MS: 255.0 [M+H]+; single peak at tR=3.98 min (System 2); Rf=0.20 (CH2Cl2/MeOH, 75/25).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)=[O:25]
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: ClCCl
Product: O=C(Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1)c1cccs1
Yield: 57.1 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.12 g, 0.50 mmol), 2-thiophenecarbonyl chloride (0.056 mL, 0.52 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (10 mL) provided 0.10 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylthiophene-2-carboxamide. MS (ESI) m/z 351; HPLC purity major: no impurities detected at 210-370 nm window; 98.7% at 240 nm (max. abs), RT=10.9 (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H22N2OS+H+, 351.15256; found (ESI, [M+H]+), 351.1516.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=2)[CH:11]=1>CC#N>[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=2)[C:11]=1[Br:8]
Reactant: Nc1cc(-c2ccc(CC(=O)O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1c(Br)c(-c2ccc(CC(=O)O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of NBS (32 mg, 0.179 mmol) in CH3CN (1 mL) was added to a mixture of [4-(7-amino-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-acetic acid (70 mg, 0.179 mmol) in CH3CN (3 mL). After stirring at room temperature for 1 h, the solvent was evaporated in vacuo and the residue was purified by prep-LC to afford titled compound (22.9 mg, 27%). LC/MS RT=3.44 min. Mass calculated for, M+H 474.05, observed 474.05.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12]1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[CH:12]3)[CH:4]=2)[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(-c2cccnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cnc(-c4cccnc4)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-(4-pyridin-3-yl-imidazol-1-yl)-benzoic acid (15 mg; 0.054 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (29 mg; 0.11), and HATU (49 mg; 0.11 mmol) were dissolved in 1 mL of DMF, and the mixture was chilled to 0° C. Diisopropylethylamine (19 μL; 0.11 mmol) was then added, the cold-bath was removed, and the mixture was stirred overnight. The mixture was then poured into water and extracted with EtOAc. The organic portion was washed with NaHCO3 and brine, and the washes were extracted once with EtOAc. The extracts were combined, dried with Na2SO4, filtered, and concentrated. Chromatography (0-6.5% MeOH/0.5% NH4OH in CH2Cl2) provided 23 mg (0.043 mmol; 80%) of Example 160. ESI MS m/z 534 [C28H31N5O4S+H]+.
Reaction SMILES: C([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][CH2:6][NH:7][C:8](=O)OC(C)(C)C)C.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)CBr>CN(C=O)C.C(OCC)(=O)C>[O:15]1[CH2:16][CH2:17][O:3][CH:4]1[CH2:5][CH2:6][NH:7][CH2:8][C:28]1[CH:27]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(CCNC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(CNCCC2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of tert-butyl (3,3-diethoxypropyl)carbamate (1.0 g, 4.05 mmol) in DMF (15 mL) was added sodium hydride (0.25 g, 6.25 mmol). The reaction mixture was stirred at room temperature for 30 minutes and 3-methoxybenzyl bromide (0.875 mL, 6.25 mmol) added. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with water and twice with brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was dissolved in ethanol (10 mL) and 4M hydrogen chloride in dioxane (10 mL) added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated at reduced pressure. The residue was loaded onto an SCX-2 cartridge and eluted with ethanol (4 column volumes) and then 10% triethylamine/ethanol (4 column volumes). The product containing fractions were combined and the solvent evaporated at reduced pressure to afford the title compound (0.543 g, 50%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[CH:6]=[CH:5][N:4]=4)[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2ccnc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2ccnc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)ccn4)CC3)c2)cc(OC)c1OC

Procedure:
2-Chloromethyl-4-(3,4,5-trimethoxyphenyl)pyridine (195 mg) and piperazine (28 mg) were reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([F:28])=[CH:26][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH:18]([C:21]([O:23]CC)=[O:22])[CH2:17][CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:29])=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:27]([F:28])=[CH:26][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:29])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-{[5-(biphenyl-4-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.615 g, 1.291 mmol) in THF (5 ml) was added potassium trimethyl silanolate (0.550 g, 4.29 mmol). The reaction was stirred overnight at ambient temperature. Then the volatiles were removed in vacuo and the resulting residue was acidified with 1N aqueous HCl and extracted with EtOAc. The organic phase was washed with water and concentrated in vacuo. Purification of the resulting residue by reverse phase HPLC eluting with 50-100% MeCN: H2O afforded the title compound as a white solid. LC-MS: calculated for C26H22F2N2O3 448.16, observed m/e 449.01 (M+H)+ (Rt 2.32/4 min). 1H NMR (500 MHz, C2D6OS): δ 7.80-7.70 (m, 4H), 7.55-7.45 (m, 4H), 7.40 (m, 1H), 7.15 (d, 1H), 5.00-4.90 (m, 1H), 2.30 (m, 1H), 2.25 (m, 2H), 2.00 (m, 2H), 1.50 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:36][C:30]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:3]=3[O:2][CH3:1])=[CH:15][CH:14]=2)=[CH:17][CH:18]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COc1cccc(OC)c1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3c(OC)cccc3OC)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-methyl-2-{4-[2-(2,6-dimethoxy-benzamido)-ethyl]-biphenyl-4'-oxy]-propionate was prepared from 4-[2-(2,6-dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 31. Yield: 20% of theory; m.p. < 20° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C([O:18][B:19](OC(C)C)[O:20]C(C)C)(C)C.Cl>O1CCCC1.[Cl-].[Na+]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:19]([OH:20])[OH:18])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.8 %

Procedure:
A solution of 10.0 g (54.9 mmol) of 4-bromobenzonitrile in 100 mL of tetrahydrofuran was cooled to −85° C. whereupon 36.0 mL (57.6 mmol) of 1.6 M solution of n-butyllithium in hexanes was added. The mixture was stirred for five minutes and 19.0 mL (82.4 mmol) of triisopropylborate was added. The mixture was stirred at −85° C. for 30 minutes then warmed to ambient temperature over one hour. To the mixture was added 35 mL of 5 N hydrochloric acid and stirring was continued for 2.5 hours. The mixture was diluted with 100 mL of saturated aqueous sodium chloride and extracted three times with 100 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from water and filtered to afford 2.0 g (25%) of the title compound.