Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:12]([CH:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:15])#[C-:13].C([O-])([O-])=O.[K+].[K+]>CO>[F:1][CH:2]([F:11])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][CH:13]=[N:12][C:14]=2[CH3:15])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(C(F)F)cc1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)F)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A mixture of Example 38C (3.68 g, 23.6 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (4.93 g, 23.6 mmol), and K2CO3 (3.26 g, 23.6 mmol) in MeOH (110 mL) was heated to reflux. After 1 hr the reaction mixture was cooled to ambient temperature and the volatiles evaporated at reduced pressure. The residue was partitioned between Et2O and H2O. The separated aqueous phase was extracted with Et2O, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 5% to 25% EtOAc/hexanes eluant; SF40-150 g column) afforded 4.39 g (89%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.80-7.73 (m, 2H), 7.69 (d, J=8.6, 2H), 7.09 (t, J=55.3, 1H), 2.40 (s, 3H). MS (DCI+) m/z 210 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Nc1n[nH]cc1-c1ccccn1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccccn4)c3n2)ccc1Cl
Yield: 69.4 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (265 mg, 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (270 mg, 69%). MS (ISP) 389.2 [(M+H)+]; mp 183° C.
Reaction SMILES: [BH4-].[Na+].[CH:3]([Si:6]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:32])[CH:15]([N:17]2[CH2:22][CH2:21][C:20]([C:24]3[CH:29]=[C:28]([Br:30])[CH:27]=[C:26]([Br:31])[CH:25]=3)([OH:23])[CH2:19][CH2:18]2)[CH3:16])=[CH:10][CH:9]=1)([CH3:5])[CH3:4]>C(O)C>[CH:36]([Si:6]([CH:3]([CH3:5])[CH3:4])([CH:33]([CH3:35])[CH3:34])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([OH:32])[C@H:15]([N:17]2[CH2:18][CH2:19][C:20]([C:24]3[CH:29]=[C:28]([Br:30])[CH:27]=[C:26]([Br:31])[CH:25]=3)([OH:23])[CH2:21][CH2:22]2)[CH3:16])=[CH:10][CH:9]=1)([CH3:38])[CH3:37]
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)N1CCC(O)(c2cc(Br)cc(Br)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[Si](Oc1ccc([C@@H](O)[C@@H](C)N2CCC(O)(c3cc(Br)cc(Br)c3)CC2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
An ice cold mixture of sodium borohydride (0.21 g, 5.56 mmol) and ethanol (50 mL) was stirred 10 min and then 1-(4-triisopropylsilyloxyphenyl)-2-(4-(3,5-dibromophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (3.55 g, 5.56 mmol in 50 mL of ethanol) was added dropwise over 15 min. The reaction was allowed to warm to ambient temperature and stir overnight. Additional sodium borohydride (0.10 g) was added and the reaction was stirred 6 h more. The white precipitate was collected and rinsed with ethanol and weighed 0.84 g. The filtrate was treated with sodium borohydride (0.10 g) and stirred overnight. The white precipitate was collected and rinsed with ethanol and weighed 2.56 g. The combined precipitate (3.40 g) was recrystallized from ethanol to afford 3.0 g (84%) of (1R*,2R*)-1-(4-triisopropylsilyloxyphenyl)-2-(4-(3,5-dibromophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol as fluffy white needles which had: mp 235-236.5° C. Analysis calculated for C29H43Br2NO3Si: C, 54.29; H, 6.76; N, 2.18. Found: C, 54.17; H, 6.50; N, 2.35.
Reaction SMILES: [Co:1].[Al].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=CC=1>>[CH:8]1([Co:1][CH:3]2[CH:8]=[CH:7][CH:6]=[CH:9]2)[CH:3]=[CH:9][CH:6]=[CH:7]1
Reactant: [Co]
Reactant: Cc1ccccc1
Agent: [Al]
Product: C1=CC([Co]C2C=CC=C2)C=C1

Procedure:
A solution of dicyclopentadienyl cobalt was prepared containing 9.92 grams of this organometallic compound and 80 milliliters of the low dielectric solvent toluene. This solution was reacted with 9.79 grams of titanium boride powder to produce a ceramic-metal compound having 0.15% cobalt. The mole fraction of cobalt (x) was 0.005. The novel intercalation compound Co0.005 TiB2 was produced.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[C:13]1([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: BrC1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OC2=CCCCC2)cc1

Procedure:
To a stirred solution of p-hydroxybenzoic acid (1.38 gm, 10 mmol) in THF (30 ml) is added sodium hydride (0.48 g, 20 mmol), followed by cyclohexenyl bromide (1.63 gm 10 mM). The mixture is heated to reflux for 12 hours. After cooling the reaction mixture is poured into ethyl acetate and extracted with 1N NaOH (3×). The combined aqueous extracts are combined, acidified to pH 2 with concentrated HCl, and extracted 3× with ethyl acetate. The combined organic extracts are dried over Na2SO4 and evaporated under reduced pressure to afford the product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([O:8]CC(O)CO)=[O:7])=[CH:4][CH:3]=1.C(N(C1C=CC(C(O)=O)=C(CCCCCCC(=O)C2C=CC=CC=2)C=1O)CC)C.C(N(CC)C1C=CC(C(C2C=CC=CC=2C(OCCCCCC)=O)=O)=C(O)C=1)C.NC1C=CC=CC=1C(OC1CC(C)CCC1C(C)C)=O>>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)OCC(O)CO)cc1
Agent: CC1CCC(C(C)C)C(OC(=O)c2ccccc2N)C1
Agent: CCCCCCOC(=O)c1ccccc1C(=O)c1ccc(N(CC)CC)cc1O
Agent: CCN(CC)c1ccc(C(=O)O)c(CCCCCCC(=O)c2ccccc2)c1O
Product: Nc1ccc(C(=O)O)cc1

Procedure:
digalloyl triolate; 2,3-dihydroxypropyl 4-aminobenzoate (lisadimate, amyl dimethyl PABA, glyceryl PABA); ethyl-4-bis(hydroxypropyl)-aminobenzoate (roxadimate); ethoxylated ethyl 4-aminobenzoate (PEG-25 PABA); hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate (diethylamino hydroxy benzoyl hexylbenzoate); (5-methyl-2-propan-2-ylcyclohexyl) 2-aminobenzoate (menthyl anthranilate, meradimate);
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]2)=O)=[CH:4][CH:3]=1.B>>[O-:1][N+:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc[n+]([O-])cc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: B
Product: O=C(OCc1ccccc1)N1CCC(CNc2cc[n+]([O-])cc2)CC1

Procedure:
Benzyl 4-{[(1-oxido-4-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate (62 mg, 0.17 mmol) was reduced with borane as described in EXAMPLE 1, step 2, to afford benzyl 4-{[(1-oxido-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate as a clear oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Br:48])[CH:43]=1>C1COCC1.CN(C=O)C.O>[Br:48][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:10](=[O:12])[C:9]#[C:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)C#CCN1CCCCC1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCCCC3)cc2c1Nc1cccc(Br)c1
Reaction time: 0.17 h
Yield: 8.5 %

Procedure:
Partially dissolved 1.23 g (7.37 mmol) 4-piperidino-2-butynoic acid in 40 ml THF and chilled to 0° C. under N2. Added 973 μl (8.4 mmol) N-methylmorpholine and 768 μl (5.9 mmol) isobutyl chloroformate. Stirred 10 minutes and added a solution of 1.00 g (2.95 mmol) 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 2 ml DMF and 10 ml THF. Removed ice bath at 15 minutes and at 5 hours added 2.95 mmol more of mixed anhydride (0.493 g acid, 487 μl NMM, and 384 μl isobutyl chloroformate), stirred overnight at 25° C. Stripped solvent, slurried residue with water, and collected solids. Boiled in ethyl acetate and collected. Dissolved in 20% methanol/chloroform and coated 5 g of silica gel. Flash chromatographed with 20% methanol/ethyl acetate, stripped solvent of desired fractions and dried in vacuo, giving 122 mg of brown solid: mass spectrum (electrospray m/e): M+H=488.0, 489.9.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.CCCCCC>[OH-].[Na+].O1CCCC1.CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Yield: 62.6 %

Procedure:
Valine (11.7 g, 100 mmol) was dissolved in 1M aqueous sodium hydroxide (100 mL), and then purified water (150 mL) and tetrahydrofuran (100 mL) were added thereto. The solution was stirred under ice-cooling, and to the solution were dropwise added 1M aqueous sodium hydroxide (100 mL) and a solution of 4-fluorobenzenesulfonyl chloride (17.5 g, 90 mmol) in tetrahydrofuran (100 mL) simultaneously. The mixed solution was stirred and allowed to react at room temperature for 18 hours. After completion of the reaction, the pH was adjusted to 2 to 3, and the solution was extracted with ethyl acetate. The extract was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to remove ethyl acetate. The residue was washed with a hexane-ethyl acetate mixture (prepared by mixing about 10 to 20 fold amount of hexane with 1 fold amount of ethyl acetate; hereinafter referred to as hexane-ethyl acetate mixture) to give N-((4-fluorophenyl)sulfonyl)-L-valine (15.5 g, 56% yield) as white crystals.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH2:46][CH2:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH2:46][CH2:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCC[C@H]2CCCCN2C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,10aR)-6-oxodecahydropyrido[1,2-a]azepin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 54 (4.7 mg, 0.021 mmol) to give a white solid (12 mg, 91% yield). Anal. Calcd. for C41H54N4O6S m/z 730.4. found: 731.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.07 (12H, m), 5.33 (1H, t, J=4.7 Hz), 5.15-5.08 (1H, m), 5.05-4.95 (1H, m), 4.83-4.72 (1H, m), 4.15 (1H, d, J=11.5 Hz), 3.88-3.77 (1H, m), 3.68 (3H, s), 3.15 (1H, ddd, J=14.2, 11.1, 2.7 Hz), 2.90-2.68 (6H, m), 2.51-2.35 (3H, m), 2.08-1.99 (2H, m), 1.85-1.42 (20H, m), 1.06-0.90 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[C:15]2[C:21](=[CH:22][N:23]=1)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17][N:16]2[CH:26]([CH3:28])[CH3:27])[C:6](O)=[O:7].[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[C:15]2[C:21](=[CH:22][N:23]=1)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17][N:16]2[CH:26]([CH3:28])[CH3:27])[C:6]([NH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:7]
Reactant: NCCN1CCCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCN2CCCCC2)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the hydrochloride salt of 3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-9-yl)amino]benzoic acid (Example 204; 127 mg, 0.33 mmol) and 1-(2-aminoethyl)piperidine (Aldrich, 54 uL, 0.38 mmol) and DIPEA (157 uL, 0.9 mmol) in anhydrous DMA (10 mL) at room temperature under nitrogen was added HATU (126 mg, 0.33 mmol) as a solid and the resulting solution stirred at room temperature overnight. The reaction mixture was loaded onto a SCX-3 column pre-wet with Methanol and the column washed with Methanol. The column was eluted with Ammonia in Methanol and product containing fractions evaporated. The resultant material was dissolved in dichloromethane and chromatographed with 2-5-10-20% methanol/dichloromethane followed by 7N ammonia/methanol. Evaporation of product containing fractions gave a yellow foam which was purified by reverse phase HPLC to yield the title compound as an off white gum (75 mg, 46%)
Reaction SMILES: [NH2:1][C@H:2]([CH3:30])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[CH3:30])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@H]1O
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)NC(=O)[C@H](O)CCO
Yield: 73 %

Procedure:
The procedure described in Example 63 was repeated using 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 73% yield; NMR spectrum (DMSO-d6) 1.22 (d, 3H), 1.46-1.61 (m, 1H), 1.72-1.87 (m, 1H), 3.40-3.54 (m, 2H), 3.84-3.97 (m, 1H), 4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 5.35 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25-7.38 (m, 2H), 7.53 (dd, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 543.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.CNC1CCCCC1NC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: Cc1cn[nH]c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2cnc(N)nc2)c1

Procedure:
A suspension of 4-methyl-1H-pyrazole (0.72 g, 0.0088 mol), 5-bromopyrimidin-2-amine (1.3 g, 7.3 mmol), copper(I) iodide (58.2 mg, 0.306 mmol), N,N′-dimethylcyclohexane-1,2-diamine (0.193 mL, 1.22 mmol), potassium carbonate (1.77 g, 12.8 mmol) in N,N-dimethylformamide (5.0 mL) was irradiated under microwave at 180° C. for 1 h. After cooling, the mixture was purified by chromatography on silica gel with methanol in methylene chloride (0-10%) to afford the desired product. LCMS: (M+H)=176.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:35])[NH:18][C@@H:19]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH:20]([O:24][CH2:25][CH3:26])OCC)[C@@H:15]2[CH2:36][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:27][C:28](=[O:29])[O:30][C@H:20]2[O:24][CH2:25][CH3:26])[C@@H:15]2[CH2:36][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (1R,3S,4S)-3-((S)-1-tert-Butoxycarbonylmethyl-2,2-diethoxy-ethylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (635 mg) in dichloromethane (3 ml) was cooled to 0° C. under nitrogen. Trifluoroacetic acid (0.7 ml) was then added and the mixture stirred at 0° C. for 15 minutes, then warmed to ambient temperature and stirred until the reaction was complete by TLC. The mixture was then diluted with dichloromethane (10 ml) and saturated aqueous sodium bicarbonate solution (14 ml). The organic phase was then removed and washed with 1:1 saturated aqueous sodium bicarbonate/brine (8 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. This afforded the sub-title compound as a mixture of epimers at the ketal centre. The epimers were separated on silica gel, eluting with 30% 2-butanone/petrol. Syn-isomer (oil) (115 mg, 23%); 1H NMR (400 MHz, d-6 DMSO) δ 0.80-1.91 (10H, m), 2.35-2.79 (2H, m), 3.56 (1H, m), 3.66-3.80 (2H, m), 4.18 (1H, m), 4.59 (1H, m), 4.94-5.11 (2H, m), 5.53 (1H, d), 7.20-7.40 (5H, m), 8.18 (0.5H, d), 8.27 (0.5H, d); MS ES+403.31 (100%), ES−401.37 (15%); Anti-isomer (oil) (103 mg, 20%); 1H NMR (400 MHz, d-6 DMSO) δ 0.80-1.85 (10H, m), 2.25-2.60 (1H, m), 2.95 (1H, m), 3.42 (1H, m), 3.5-3.75 (2H, m), 4.88-5.15 (3H, m), 7.21-7.40 (5H, m), 8.50 (0.4H, d), 8.59 (0.6H, d).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C1NCC[C@@H]1O
Product: O=C1NCC[C@H]1Oc1ccc(OCc2ccccc2)cc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 4-benzyloxy-phenol provided the subtitle compound. MS ESI+: m/z=284 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][CH:68]([CH3:72])[CH2:69][O:70][CH3:71])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][CH:68]([CH3:72])[CH2:69][O:70][CH3:71])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: COCC(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: COCC(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-1-methyl-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=565, obsd.=565).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH3:10])[CH:8]=1)([O-])=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][CH:33]([CH2:37][CH2:38][CH3:39])[C:34](O)=[O:35])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([CH:9]([N:7]2[CH:8]=[C:4]([NH:1][C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=3)[CH2:37][CH2:38][CH3:39])[N:5]=[CH:6]2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CC(c1ccc(C(F)(F)F)cc1)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)c2ccc(C(F)(F)F)cc2)cn1

Procedure:
4-Nitro-1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazole was reduced and then coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 509.5 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:54])[C:32]([C:52]#[N:53])=[CH:33][C:34]([N:37]4[CH2:42][C@@H:41]([CH3:43])[N:40](C(OC(C)(C)C)=O)[C@@H:39]([CH3:51])[CH2:38]4)([CH3:36])[CH3:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:33][C:34]([N:37]4[CH2:42][C@@H:41]([CH3:43])[NH:40][C@@H:39]([CH3:51])[CH2:38]4)([CH3:36])[CH3:35])[C:52]#[N:53])=[O:54])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: C[C@@H]1CN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The (2S,6R)-tert-butyl 4-(5-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)-2,6-dimethylpiperazine-1-carboxylate (103.5 mg, 0.1400 mmol) was dissolved in 4N HCl in dioxane, and stirred at rt for 3 hours. The solvent was removed and 2 mL of MeOH was added to the residues. The mixture was neutralized to pH around 7-8 and extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and the solvent evaporated to get pure product 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile as a white solid. MS (pos. ion) m/z: 638 (M+1).