Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:56])[CH2:7][C@@:8]1([CH3:55])[C:12]2=[N:13][CH:14]=[C:15]([N:18]([CH2:29][CH:30]=[CH2:31])[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:16](=[O:17])[N:11]2[C@@H:10]([C:32](=[O:54])[NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([NH:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[NH:42])=[CH:37][CH:36]=2)[CH2:9]1)(C)(C)C>O1CCOCC1.Cl>[CH2:29]([N:18]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C:15]1[C:16](=[O:17])[N:11]2[C@@H:10]([C:32](=[O:54])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([NH:43][C:44]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)=[O:45])=[NH:42])=[CH:37][CH:36]=3)[CH2:9][C@:8]([CH2:7][C:6]([OH:56])=[O:5])([CH3:55])[C:12]2=[N:13][CH:14]=1)[CH:30]=[CH2:31]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)O
Yield: 102 %

Procedure:
A solution of intermediate 38d (262.3 mg, 0.34 mmol) in 5 mL 4M HCl dioxane was stirred at rt for 2 h. The solvent was removed in vacuo, then the compound was triturated with ether to afford 245 mg (100%) of intermediate 39a. MS (ESI) 707.4 (M+H+), 705.3 (M−H+).
Reaction SMILES: [I-].[Br:2][C:3]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:4]=1[CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[C:33]([O:37][C@@H:38]([C:44]1[C:45]([CH3:87])=[N:46][C:47]2[N:48]([N:82]=[C:83]([CH:85]=O)[CH:84]=2)[C:49]=1[N:50]1[CH2:55][CH2:54][C:53]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]([O:64][Si:65]([C:78]([CH3:81])([CH3:80])[CH3:79])([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH3:63])([CH3:56])[CH2:52][CH2:51]1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Br:2][C:3]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:4]=1[CH2:5][CH:6]=[CH:85][C:83]1[CH:84]=[C:47]2[N:46]=[C:45]([CH3:87])[C:44]([C@H:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:49]([N:50]3[CH2:55][CH2:54][C:53]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]([O:64][Si:65]([C:78]([CH3:79])([CH3:80])[CH3:81])([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C:72]4[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=4)[CH3:63])([CH3:56])[CH2:52][CH2:51]3)[N:48]2[N:82]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3Br)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.6 %

Procedure:
To a suspension of (2-bromo-4-fluorophenethyl)triphenylphosphonium, iodide salt (705 mg, 1.193 mmol) in THF (8 ml) at 0° C. was added NaH (48.9 mg, 1.223 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to −78° C. and (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (460 mg, 0.597 mmol) dissolved in THF (8 ml) was added dropwise and the mixture was stirred at −78° C. for 1 h then warmed to rt and stirred 1 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-bromo-4-fluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (500 mg, 0.523 mmol, 88% yield) as inseparable mixture of E and Z isomers. LCMS (M+2H)=957.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].CN(C)C=O.Br[CH2:21][CH2:22][OH:23]>O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:21][CH2:22][OH:23]
Reactant: Oc1ccccc1Br
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1ccccc1Br
Temperature: 50 °C
Yield: 93.1 %

Procedure:
Potassium carbonate (23.8 g) and 2-bromophenol (14.9 g) were mixed with dimethylformamide (150 ml). 2-Bromoethanol (12.9 g) was added and the mixture heated to 50° C. for 18 h. The mixture was cooled and added to water (1500 ml). The product was extracted into diethyl ether (×3) and washed twice with dilute sodium hydroxide solution. Evaporation gave 2-(2-bromophenoxy)ethanol (17.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:32])[N:11]([S:13]([C:16]3[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH:41]([OH:46])[C:42]([F:45])([F:44])[F:43]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:40][CH:41]([OH:46])[C:42]([F:45])([F:44])[F:43])[C:10](=[O:32])[N:11]([S:13]([C:16]3[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:30])([F:29])[F:31])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: OC(CBr)C(F)(F)F
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)nn1S(=O)(=O)c1ncnn1Cc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1n(S(=O)(=O)c2ncnn2Cc2ccccc2C(F)(F)F)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
50 mg (0.10 mmol) of the compound from Example 95A together with 50 mg (0.16 mmol) of cesium carbonate were dissolved in 0.5 ml of DMF, and 30 mg (0.16 mmol) of 3-bromo-1,1,1-trifluoropropan-2-ol were added. The mixture was then stirred at 75° C. for 8 h. For work-up, the reaction mixture was diluted with 0.5 ml of acetonitrile and directly purified chromatographically [Method 19]. This gave 15 mg (22% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:7]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[NH:35][CH:36]=[CH:37][C:38](=[O:40])[N:39]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24]([NH:30][CH2:31][CH2:32][NH:33][C:34]4[NH:35][CH:36]=[CH:37][C:38](=[O:40])[N:39]=4)=[O:25])[CH:21]=[CH:20][N:19]=3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: NCCNc1nc(=O)cc[nH]1
Reactant: COC(=O)c1ccnc(NCCCN2CCN(c3cc(Cl)ccc3OC)CC2)n1
Solvent: CCCCO
Product: COc1ccc(Cl)cc1N1CCN(CCCNc2nccc(C(=O)NCCNc3nc(=O)cc[nH]3)n2)CC1

Procedure:
1.89 g of (4.5 mmols) of methyl 2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]propyl]amino]-pyrimidine-4-carboxylate and 0.77 g (5 mmols) of 2-[(2-aminoethyl)amino]pyrimidin-4(1H)-one in 5 ml of n-butanol are introduced into a 25 ml, round bottomed flask. The mixture is heated at the reflux temperature of the solvent for 15 hours and then the solvent is evaporated under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[Cl:24])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[Cl:24])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Cc1ccc(Cl)c(Cc2cc(Cl)ncn2)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2c(Cl)ccc(C)c2F)ncn1
Temperature: 25 °C
Yield: 106.8 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.06 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was then stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2-chloro-5-methyl-6-fluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-(2-butynyloxy)-6-(2-chloro-5-methyl-6-fluorobenzyl)pyrimidine (the present compound (121)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:18]([F:19])([F:20])[F:21])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C#Cc2ccncc2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCc2ccncc2)c(C(F)(F)F)c1
Yield: 84.4 %

Procedure:
In 20 mL of ethanol, 1.3 g (4.45 mmol) of 4-(4-nitro-2-(trifluoromethyl)phenylethynyl)pyridine was dissolved and stirred on 100 mg of 10% palladium carbon overnight at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated and the residue was purified by a silica gel column (n-hexane:ethyl acetate=1:2) to obtain 1.0 g (85%) of a target product as a pale yellow oil.
Reaction SMILES: [CH:1]([O:6]C)([O:4][CH3:5])OC.[Cl:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]([O:25][CH3:26])=O)[CH:10]=1.[OH-].[Na+].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[Cl:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2/[C:22](=[CH:23]\[O:25][CH3:26])/[C:1]([O:4][CH3:5])=[O:6])[CH:10]=1
Reactant: COC(OC)OC
Reactant: COC(=O)Cc1ccccc1Oc1cc(Cl)ncn1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Under the dried nitrogen atmosphere, to a reaction flask were added 150 mL of dichloromethane and 11.4 g of titanium tetrachloride, and then 6.4 g of trimethyl orthoformate was further added under violent stirring. After being stirred at room temperature for 1 hr, the mixture was cooled to −5° C., followed by adding thereto 13.9 g of methyl 2-(2-(6-chloropyrimidin-4-oxy)phenyl)acetate. The resultant was stirred for 30 min, and then 12.1 g of triethylamine was added and the resultant was stirred for 1 hr. The resulting reaction mixture was washed with 40 mL of 10% hydrochloric acid, dried with anhydrous magnesium sulfate and evaporated under vacuum to obtain a brown viscous substance. The brown viscous substance was dissolved in 100 mL of hot toluene, cooled to room temperature and then treated with 0.9 g of benzyltriethylammonium chloride, 15 g of 20% sodium hydroxide aqueous solution and 12.6 g of dimethyl sulfate. After that, the mixture was stirred at room temperature for 5 hrs, followed by being heated to 50° C., and the reaction went on under stirring for another 1 hr. The resulting mixture was washed with 50 mL of water, evaporated under reduced pressure and purified with flash column chromatography to obtain 14.6 g pale yellow solid. The yield was 91%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH:39](Br)[CH3:40])(=[O:37])[CH3:36]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:39]([O:38][C:35](=[O:37])[CH3:36])[CH3:40])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: CC=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-propenyl)-3-cephem-4-carboxylic acid (190 mg, 0.45 mmole) and potassium carbonate (75 mg, 0.54 mmole) in DMF (5 ml) was added at 5° C. 1-bromoethyl acetate** (90 mg, 0.54 mmole). The mixture was stirred at 5° C. for 1.5 hours and diluted with ethyl acetate (20 ml). The dilute was washed successively with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (5 g) with 1% methanol in chloroform. The desired fractions were combined and concentrated. The residue was dissolved in dioxane and lyophilized to yield 103 mg (45%) of the title compound as its dioxane solvate. Mp. 105°-110° C. Estimated purity 85% (by HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)=[CH:16][C:15]=2[CH2:27][NH:28][CH2:29][CH3:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[CH:22][C:23]([F:26])=[CH:24][N:25]=3)=[CH:16][C:15]=2[CH2:27][N:28]([C:35]([CH:32]2[CH2:34][CH2:33]2)=[O:36])[CH2:29][CH3:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(-c2ncc(F)cn2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ncc(F)cn3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-ethylaminomethyl-4′-(5-fluoro-pyrimidin-2-yl)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:28])[NH:9][CH:10]([CH2:26][OH:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:13]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:29]1COCC1>CCOC(C)=O>[C:3]([O:7][C:8](=[O:28])[NH:9][CH:10]([CH2:26][O:27][CH3:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:13]=1)([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCC(Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (55 mg, 1.31 mmol, 60% by wt suspension in mineral oil) was added at 0° C. to a solution of [2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (0.5 g, 1.31 mmol) in 5 mL anhydrous THF and stirred for 20 min at 0° C. Mel (0.37 g, 2.63 mmol) was added to the reaction mixture and stirred for 6 h at room temperature. The reaction mixture was diluted with 5 mL EtOAc, and washed with water, brine and dried over Na2SO4. Solvent was removed under vacuum and silica gel chromatography (EtOAc: Hexanes) gave (R)-[[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-methoxymethyl-ethyl]-carbamic acid tert-butyl ester (0.38 g). The Boc protecting group was removed by stirring the compound in 4M HCl in dioxane (5 ml) for 30 min. Evaporation of the solvent under vacuo gave (R)-2-(3′-chloro4′-fluoro-biphenyl-4-yl)-1-methoxymethyl-ethylamine hydrochloride.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.O=[N+]=O.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Agent: O=[N+]=O
Product: O=[N+]([O-])c1ccccc1

Procedure:
The most common reagent used in conventional methods for preparing nitrobenzene is nitric acid or a mixed acid, typically, a mixed solution of concentrated nitric acid and concentrated sulfuric acid, oleum or fuming sulfuric acid. The process generally includes initially forming a nitronium ion, NO2+ by the reaction of nitric acid with concentrated sulfuric acid, as follows: HNO3+2H2SO4→NO2++H3O++2HSO4− The nitronium ion then reacts with benzene to form nitrobenzene, according to the following reaction:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[F:27][C:26]([F:29])([F:28])[CH2:25][CH2:24][CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: FC(F)(F)CCCBr
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCC(F)(F)F)CC1)O2

Procedure:
Compound 141 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-bromo-1,1,1-trifluorobutane and conditions outlined in procedure V. LCMS: 412 [M+H]; Rt=0.96 min.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:19]([Cl:30])=[CH:18][N:17]=1>>[Cl:30][C:19]1[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4O)n3)cc2CC1
Yield: 35 %

Procedure:
Analagous to Example 318b, trans-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-cyclopropyl-benzamide was prepared from 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and trans-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol in 35% yield as a foam. LCMS (m/e) 416 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.35 (s, 1H), 7.23 (m, 1H), 7.05 (m, 1H), 6.82 (s, 1H), 5.16 (m, 1H), 3.90 (m, 1H), 3.48 (m, 1H), 2.7-3.2 (m, 10H), 2.14 (m, 2H), 1.78 (m, 2H), 1.2-1.5 (m, 8H).
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]4[N:30]([CH3:31])[N:29]=[N:28][CH:27]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][CH2:33][C:34]#[C:35][CH2:36]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:32][CH2:33][C:34]#[C:35][CH2:36][N:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]3[N:30]([CH3:31])[N:29]=[N:28][CH:27]=3)[CH:17]=2)[C@@H:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC#CCCl
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2S,3S]-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine hydrochloride (270 mg) in N,N-dimethylformamide (3.0 ml) was slowly added to a solution of 1,4-dichlorobut-2-yne (189 ml) and potassium carbonate (269 mg) in N,N-dimethylformamide (5.0 ml). The solution was stirred for 18 hours at room temperature and the solvent removed under reduced pressure. To the residue was added water (40 ml) and the product was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with water, saturated brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by MPLC (40% ethyl acetate/hexane) to give [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow oil (142 mg). 1H NMR (360 MHz,CDCl3) δ 1.52 (2H, m), 2.16 (2H, m), 2.64 (1H, m), 3.00 (1H, m), 3.30 (2H, m), 3.48 (1H, br s), 3.57 (1H, s), 3.98 (3H, s), 4.11 (1H, d, J=11.0 Hz), 4.15 (1H, s) 4.52 (2H, d, J=11.0 Hz), 7.17-7.26 (4H, m), 7.40-7.47 (4H, m), 7.68 (1H, s).
Reaction SMILES: C([Li])CCC.C([Mg]Cl)(C)C.Br[C:12]1[N:17]=[CH:16][C:15]([N:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.Cl[C:38]1[C:39]2[CH2:52][CH2:51][N:50]([C:53]3[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=3)[C:40]=2[N:41]=[C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:43]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:15]2[CH:16]=[N:17][C:12]([C:38]3[C:39]4[CH2:52][CH2:51][N:50]([C:53]5[CH:54]=[CH:55][N:56]=[CH:57][CH:58]=5)[C:40]=4[N:41]=[C:42]([N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)[N:43]=3)=[CH:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(Br)nc2)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccncc3)nc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.1 %

Procedure:
To a solution of n-butyl lithium (1.56M hexane solution, 0.23 ml, 0.363 mmol) in tetrahydrofuran (2 ml), at 0° C., isopropyl magnesium chloride (2M tetrahydrofuran solution, 0.09 ml, 0.182 mmol) was added, followed by stirring for 15 minutes. To this, a solution of (6-bromo-pyridin-3-yl)-bis-(4-methoxy-benzyl)-amine (50 mg, 0.121 mmol, 1.0 equivalent) in tetrahydrofuran (1 ml) was added, followed by stirring for 1.5 hours. Zinc chloride (1M diethyl ether solution, 0.55 ml, 0.545 mmol) was added, and the temperature was raised to room temperature, followed by stirring for 1 hour. 4-Chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (38.4 mg, 0.121 mmol) was added, followed by refluxing for 2 hours. Water was added, followed by extraction with ethyl acetate, and the organic layer was washed with brine. After drying over sodium sulfate, concentration was carried out under reduced pressure. Purification by preparative TLC (dichloromethane/methanol=40/1) afforded bis-(4-methoxy-benzyl)-[6-(2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyridin-3-yl]-amine (5.3 mg, yield 7%).