Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]#[N:9].C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1>C(OCC)(=O)C.C1CCCCC1>[C:8]([C:2]1([CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2)#[N:9]
Reactant: N#CC1CC2CCC1C2
Reactant: BrCC1OCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: N#CC1(CC2OCCO2)CC2CCC1C2
Yield: 92.1 %

Procedure:
7.2 g of norbornane-2-carbonitrile are reacted with 60 mmoles of lithium diisopropylamide (prepared from 8.2 ml of diisopropylamine and 40 ml of n-butyllithium) and with 7 g of 2-bromomethyl-1,3-dioxolane in analogy to Example 1a. After chromatography on silica gel with ethyl acetate/cyclohexane (1:6) as the mobile phase, 8.0 g of the title compound are obtained as an oil.
Reaction SMILES: CO[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=O.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(Cl)Cl>O1CCCC1>[CH3:3][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1
Reactant: COC(=O)NCCc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CNCCc1ccc(OC)c(OC)c1

Procedure:
The product of (i) was reduced in dry tetrahydrofuran or diethylether in conventional manner by the addition of 3 equivalents of LiAlH4 and subsequent refluxing of the mixture for 0.5-1 hr. After cooling and filtration, the solvent was evaporated and the product obtained by first extraction of the ethereal phase at pH 4, then at pH 10 with methylene chloride. Drying and evaporation of the solvent yielded 50-60% nearly pure oily product.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH2:9]OC(=O)C3C=CC=CC=3C(O)=O)[CH2:7][S:8][C@H:3]12.[SH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O>C(#N)C>[NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH2:9][S:27][C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3C(=O)O)CS[C@H]12
Reactant: Cn1nnnc1S
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A 3.5 ml portion of acetonitrile was added to 0.946 g of 7-amino-3-(2-carboxybenzoyloxy)methyl-3-cephem-4-carboxylic acid and 0.32 g of 5-mercapto-1-methyl-1H-tetrazole, and the mixture was cooled over a dry-ice/ethanol bath, followed by adding through a dropping funnel 3.71 g of DCPA to it with stirring and rinsing the funnel with 1.0 ml of acetonitrile. The external bath was removed, and the reaction mixture was warmed to 0° C., whereby the starting materials dissolved. The solution was stirred at 14° to 16° C. for 40 minutes to allow the reaction to proceed, and the reaction solution was cooled with ice, and poured into ice-water, which was placed in a refrigerator overnight. The precipitate was filtered out and washed with 10 ml of water, and the filtrate and washing were combined and adjusted to pH 4.0 with 25% aqueous ammonia under ice cooling. The precipitated powder was recovered by filtration, washed with water and acetone successively, and dried, thereby affording 0.710 g (86.5% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR values of the product were in accordance with those of the authentic sample.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[CH:12]1([N:15]2[C:19]([CH2:20][CH:21]([CH3:25])[C:22](O)=O)=[CH:18][N:17]=[C:16]2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O>O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:22]([CH:21]([CH3:25])[CH2:20][C:19]3[N:15]([CH:12]4[CH2:14][CH2:13]4)[C:16]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)=[N:17][CH:18]=3)[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(Cc1cnc(-c2ccncc2)n1C1CC1)C(=O)O
Reactant: N=C(NO)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cc1cnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Temperature: 120 °C
Yield: 38.4 %

Procedure:
3-chloro-N-hydroxy-benzamidine (486 mg, 2.85 mmol), 3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionic acid (702 mg, 2.59 mmol), EDCl (546 mg, 2.85 mmol) and HOBt hydrate (385 mg, 2.85 mmol) were mixed with DMF (20 ml) and stirred o.n. at r.t. The reaction was diluted with water and extracted with EA. The combined organic phase was successively washed with sat. aq. sodium bicarbonate, brine, dried (Na2SO4), filtered and concentrated in-vacuo. The residue was heated in DMF (10 ml) at 120° C. for 2 h. The reaction mixture was cooled to r.t., diluted with EA (50 ml), successively washed with water and brine, dried (Na2SO4), filtered and concentrated in-vacuo. The crude was purified via column chromatography using 2% MeOH in DCM to isolate the title compound (404 mg). 1H-NMR: 8.69 (dd, 2H), 8.09 (m, 1H), 7.96 (d, 1H), 7.67 (dd, 2H), 7.46 (m, 2H), 6.94 (s, 1H), 3.66 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 3.16 (m, 1H), 1.59 (d, 3H), 1.19 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH3:13].[OH-:21].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[C:13](=[O:21])[CH2:12][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: [OH-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: O=C(Cc1ccccc1)C(O)c1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitrobenzaldehyde is reacted with acetophenone and sodium hydroxide in ethanol to produce 3-(p-nitrophenyl)-3-hydroxy-1-phenyl propanone. The resulting compound is reacted with KHSO4 to obtain p-nitrochalcone. p-Nitrochalcone is hydrogenated in the presence of platinum catalyst to produce 3-(p-aminophenyl)-1-phenyl propanone. The resulting compound is reacted with potassium hydroxide and hydrazine in triethylene glycol to produce p-aminodiophenylpropane. p-Aminodiphenylpropane is reacted with fuming nitric acid and acetic acid anhydride to obtain 1-(p-aminophenyl)-3-p-nitrophenyl)-propane.
Reaction SMILES: [C@H:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C[Si]([Br:14])(C)C.CS(C)=O.C(N(CC)C(C)C)(C)C.C1C=C(NS(C2C=CC(N/N=C3/C=CC(C(C(O)=O)=C/3)=O)=CC=2)(=O)=O)N=CC=1>C(Cl)(Cl)Cl>[Br:14][C@H:4]1[C@@H:5]2[CH2:6][C@@H:1]([C:7](=[O:9])[O:8]2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)Br
Reactant: O=C(O)[C@@H]1CC=CCC1
Agent: O=C(O)C1=C/C(=N\Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)C=CC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: O=C1O[C@H]2C[C@@H]1CC[C@H]2Br

Procedure:
(S)-Cyclohex-3-enecarboxylic acid (1.98 g, 15.7 mmol) ([α]D=−92.7° (c=1, CHCl3)=97.5% e.e., resolved by the method of Schwartz et al, J. Am. Chem. Soc., 100, 5199, (1978)) was reacted with trimethylsilyl bromide (4.10 mL, 31.3 mmol), DMSO (2.23 mL, 31.3 mmol), and N,N-diisopropylethylamine (4.45 mL, 31.3 mmol) (by a modification of the method of Iwata et al, Heterocycles., 31, 987 (1990)) to give a white solid, (2.91 g, 14.2 mmol, 90%);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH2:26])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1.CCN(C(C)C)C(C)C.O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[C:15]([F:14])[CH:16]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(-n2cccn2)c(F)c1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (280 mg, 1.27 mmol) and 3-fluoro-4-(1H-pyrazol-1-yl)benzenamine (230 mg, 1.30 mmol) in CH3CN (8 mL) at room temperature, DIEA (0.442 mL, 2.54 mmol) was added. The mixture was stirred at room temperature for 48 h. Water (15 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(3-fluoro-4-(1H-pyrazol-1-yl)phenylamino)pyrimidine-5-carboxylate as a solid (275 mg). MS 362.3 and 364.3 (M+H, Cl pattern)
Reaction SMILES: [C:1]([O:5][C:6]([O:8][Si](C(C)(C)C)(C)C)=[CH2:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:23]([CH3:35])[C@@H:24]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:25](OC)[O:26][CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.B(F)(F)F.CCOCC>ClCCl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[CH2:8][C@@H:25]([O:26][CH3:27])[C@@H:24]([N:23]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:35])[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: COC(OC)[C@H](C1CCCC1)N(C)Cc1ccccc1
Agent: FB(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: CO[C@H](CC(=O)OC(C)(C)C)[C@H](C1CCCC1)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To (1-tert-butoxyvinyloxy)(tert-butyl)dimethylsilane (7) (9.9 g, 43.0 mmol) in dichloromethane (80 mL) was added (S)—N-benzyl-1-cyclopentyl-2,2-dimethoxy-(S)—N-benzyl-1-cyclopentyl-2,2-dimethoxy-N-methylethanamine (6) (8.0 g, 28.8 mmol) followed by a solution of BF3. ether (3.6 mL) in DMF (4.9 mL) and dichloromethane (20 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. After concentrated, the residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate, 10:1) to give product 8 (4.3 g, 66%). LC-MS: 361.3 [M+H+]+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[CH2:3]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.596 g, 2.62 mmol) in methanol (10 mL) was added with potassium carbonate (0.724 g, 5.24 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with dimethyl (1-diazo-2-oxopropyl)phosphonate (0.500 g, 2.62 mmol), and the mixture was stirred at room temperature for additional 4 hours. The reaction mixture was concentrated, and then added with water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.393 g, 67%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:25]=[CH:24][C:18]3[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38]([C:30]1[CH:31]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=4[CH:16]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:27])[CH:3]=2)[CH:33]=[CH:34][C:29]=1[F:28])=[O:39])[CH3:42]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4c(c3)oc(=O)n4C)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 133, step 3) by Suzuki coupling with 4-fluoro-3-ethoxycarbonylphenylboronic acid [CAS Reg. No. 874219-36-0]. The title compound was used without further analysis.
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[Br-:1].[CH3:7][N:4]1[CH2:5][CH2:6][CH:2]([P+:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]1=[O:8]
Reactant: CN1CCC(Br)C1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Product: [Br-]
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A solution of (±)3-bromo-1-methyl-2-pyrrolidone (1.40 g, 7.86 mmol) and triphenylphosphine (2 g, 7.62 mmol) in THF (50 ml) was refluxed for 2 days. After cooling to RT the white solid formed was filtered, washed thoroughly with THF and dried to give pure title compound (900 mg, 2.04 mmol, yield 26.8%).
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])[CH3:17])=[CH:12][CH:11]=1)#[N:9].[CH:28]1[CH:33]=[CH:32][C:31]([O:34][C:35](Cl)=[S:36])=[CH:30][CH:29]=1.O>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:23])[CH3:24])[NH:21][C:35]([O:34][C:31]2[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH3:17])=[CH:26][CH:27]=1)#[N:9]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=S)Oc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 73 %

Procedure:
0.4 g of N-methyhnorpholine was added to a suspension containing 1.1 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 40 ml of methylene chloride, at -15° C. After 0.7 g of phenyl chlorothionoformate was added to the mixture at -15° C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a yellow glutinous substance (yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].C1COCC1.[CH3:26][NH2:27]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:27][CH3:26])=[O:16])=[C:5]2[OH:20]
Reactant: CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.10 g, 3732 μmol, see Example 2) was dissolved in 2M methanamine in THF (9331 μL, 18661 μmol). The resulting mixture was stirred at 60° C. for 16 hours and then diluted with 100 mL of EtOAc. The resulting mixture was added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 20 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4 and concentrated in vacuo to give the title compound (131 mg) as a white solid after purification via preparatory LC. MS m/e=280 (M+H)+. Calculated for C14H14ClNO3 279.07.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(F)ccc1C
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
Trimethylaluminium (2M in toluene) (0.556 mL, 1.11 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (143 mg, 1.11 mmol) in toluene (10 mL), under nitrogen at 0° C. The resulting solution was allowed to stir at this temperature for a further 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AK4) (466 mg, 0.74 mmol) in toluene (5 mL) was added slowly to the mixture at 0° C. The reaction mixture was then heated to 100° C. and was stirred for 6 hours using the microwave. The reaction mixture was allowed to cool to ambient temperature, then evaporated to afford a gum. This was dissolved in EtOAc (75 mL), and washed sequentially with Rochelle's solution (20 mL), and water (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% EtOAc in isohexane to afford the product (390 mg, 72.6%). 1H NMR (400 MHz, DMSO) δ 0.88 (9H, s), 2.03 (3H, s), 3.82-3.67 (4H, m), 4.05 (1H, m), 4.15 (1H, m), 6.00 (1H, m), 7.45-7.31 (8H, m), 7.50 (1H, t), 7.60 (4H, m), 7.87 (1H, dd), 8.02 (1H, d), 8.40 (1H, d), 8.51 (1H, s), 8.56 (1H, s), 11.25 (1H, s); m/z (ES+) (M+H)+=725; HPLC tR=3.63 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13].OO.ClCCl.C(OCC)(=[O:35])C>C(O)(=O)C>[OH:1][CH2:2][C:3]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][S:7]([CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13])=[O:35]
Reactant: CCOC(C)=O
Reactant: CC(CO)(CCCSCCCC(C)(CO)c1ccccc1)c1ccccc1
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(CO)(CCCS(=O)CCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 5-(5-hydroxy-4-methyl-4-phenylpentylsulfanyl)-2-methyl-2-phenylpentan-1-ol (3.37 g, 8.14 mmol) in glacial acetic acid (100 mL) was added 50% aqueous hydrogen peroxide solution (0.55 g, 8.14 mmol) drop-wise at rt over 5 min. The reaction mixture was stirred at rt for 3 h, while the reaction progress was monitored by TLC (dichloromethane/ethyl acetate=2/1). The reaction mixture was concentrated to yield a crude product (3.5 g) that was purified by column chromatography on silica gel (dichloromethane, then dichloromethane/ethyl acetate=1/1, followed by dichloromethane/ethanol=1/1). The product-containing fractions were concentrated and dried at 120° C. under high vacuo for 2.5 h to give 5-(5-hydroxy-4-methyl-4-phenylpentylsulfinyl)-2-methyl-2-phenylpentan-1-ol (2.55 g, 71%) as colorless, viscous oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.30 (m, 8 H), 7.20 (m, 2 H), 3.66-3.56 (m, 4 H), 2.54-2.38 (m, 4 H), 2.13 (br., 2 H), 1.90-1.43 (m, 8 H), 1.33 (s, 6 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 144.56, 128.68, 126.66, 126.62, 126.62, 71.82, 71.57, 52.92, 43.38, 43.35, 37.56, 37.43, 22.14, 21.77, 17.87, 17.71. HRMS (LSIMS, gly): Calcd. for C24H35O3S1 (MH+): 403.2307, found: 403.2295.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10](Cl)(Cl)=[O:11].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:10]([NH:9][C:3]4([CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[O:11])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: O=C(Cl)Cl
Reactant: CC1(N)CCCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3(C)CCCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 1-methylcyclohexanamine hydrochloride, phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=464.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13]COC)[CH:8]=1)[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1cccc(OCOC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(3-methoxymethoxy-phenyl)-propionic acid ethyl ester in the dichloromethane was added dropwise TFA (150 mL) at 0□. The reaction mixture was stirred 1 h at 0°, and solid sodium bicarbonate (200 g) was added very slowly. The resulting mixture was poured into ice water very slowly and extracted with EtOAc. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1 to 4:1) to afford the product as colorless oil. (19.0 g, 70.4% 2 steps)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A solution of 2,4-difluorophenol (5.39 g, 41.4 mmol) in dimethylformamide (34.5 mL) at 10° C. under nitrogen was treated portionwise with sodium hydride (1.657 g, 41.4 mmol), stirred for 15 minutes and treated portionwise with 4-fluoro-3-nitrobenzenesulfonamide (2.28 g, 10.36 mmol). The solution was stirred at ambient temperature for 1.5 hours, diluted into ethyl acetate and carefully quenched with 0.5 M HCl to a constant pH of 6. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. The residue was triturated in 3:1 hexane/ethyl acetate to afford the title compound (3.24 g, 95%).