Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[NH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:10])[CH3:9].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1.O>CN(C)C(=O)C>[C:41]([O:40][C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]([C:8]([OH:7])([CH3:10])[CH3:9])[N:12]=[C:13]2[CH2:21][CH2:22][CH3:23])=[CH:27][CH:28]=1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
3.00 g of potassium t-butoxide were added, whilst ice-cooling, to a solution of 6 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 40 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 10 minutes, after which a solution of 9.00 g of t-butyl 4'-bromomethylbiphenyl -2-carboxylate in 40 ml of N,N-dimethylacetamide was added. After the reaction mixture had been stirred at room temperature for 1 hour and then at 50° C. for 2 hours, it was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 11.6 g of the title compound as a solid, softening at above 85° C.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)#[N:22].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 79.4 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.15 g, 0.56 mmol) was reacted with 4-cyanobenzaldehyde (0.07 g, 0.56 mmol) in the presence of glacial acetic acid (0.033 g, 0.56 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.042 g, 0.67 mmol) in methanol (5 ml) (Procedure D) to give compound 16c (0.17 g, 80%) as an oil.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C(N(CC)CC)C.O>CS(C)=O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: COC(=O)CN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)CNc1cc([N+](=O)[O-])ccc1C#N
Yield: 97.8 %

Procedure:
A solution of 2-fluoro-4-nitro-benzonitrile (16.6 g, 0.1 mol), glycine methyl ester (16 g, 0.125 mol, 1.25 eq.) and triethylamine (20 g, 0.2 mol) in DMSO (250 mL) was stirred at 70° C. for 12 hours. Water (2 L) was added and the solid precipitate was collected by filtration. Washed with ether and dried to give (2-cyano-5-nitro-phenylamino)-acetic acid methyl ester (23 g, 97.8 mmol, 98%): 1H NMR (300 MHz, CDCl3) δ 7.61 (dd, 2H), 7.40 (d, 1H), 4.10 (d, 2H), 3.87 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClN1C(=[O:25])CCC1=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-n2ccc3ccccc32)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1ccc(N2C(=O)Cc3ccccc32)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-Fluoro-4-methoxyphenyl)indole (7.0 g, 0.029 mole), N-chlorosuccinimide (98%, 4.14 g, 0.0304 mole) and CH2Cl2 (200 ml) were combined and stirred 2 hours at 25° C., producing a solution which was evaporated in vacuo to a semisolid. The latter was diluted with 120 ml CH3CO2H and warmed to 70°. H3POl4 (85%, 31.3 ml) was added in one portion, the mixture was refluxed 1 hour, cooled, gasified with saturated Na2CO3 and extracted 4×100 ml ethyl acetate. The organic layers were combined, dried over MgSO4, and evaporated in vacuo to solids (7.9 g). Chromatography on silica gel, (7.5×15 cm) eluting with CH2Cl2 in 1 liter fractions gave, on evaporation of combined fractions 4-13, purified title product, 3.8 g, m.p. 133°-136°.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN1CCOCC1>CN1C(=O)CCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of 3-fluoro-5-amino-6-nitrotoluene (10 g, 58.79 mmol) in anhydrous NMP (160 mL) under nitrogen was added BOC-piperazine (39 g, 209.4 mmol) and 4-methylmorpholine (25.9 mL). The resulting dark solution was heated to reflux for 72 h, cooled to room temperature and diluted with ethyl acetate (4000 mL). The organic layer was washed with water (8×1500 mL), brine (1×1500 mL), dried over sodium sulfate and evaporated in vacuo. The resulting dark oil was dissolved in boiling absolute ethanol (800 mL) and concentrated to a total volume of 400 mL and left to stand overnight at room temperature. The solution was further cooled to −20° C. for 5 h and the resulting solid was filtered off and dried in vacuo to give 16.3 g (83%) of a light yellow solid. 1H NMR (500 MHz, CDCl3) δ 6.16 (brs, 1H), 6.04 (brs, 1H), 3.70-3.60 (m,4H), 3.38-3.25 (m, 4H), 2.53 (s, 3H), 1.48 (s, 9H); LCMS (M+H)+ m/z 337.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][OH:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:21][CH2:20][CH2:19][CH2:18][C:17]#[C:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1cccc2ccccc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC#Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
A solution of 0.85 g (7.42 mmol) of methanesulphonyl chloride in 5 ml of dichloromethane is added dropwise to a solution, cooled with an ice bath, of 1.2 g (5.71 mmol) of 5-(naphth-1-yl)pent-4-yn-1-ol, obtained in stage 3.1., and of 1.6 ml (11.4 mmol) of triethylamine in 12 ml of dichloromethane. The mixture is stirred at 0° C. for 1 hour and then at ambient temperature for 2 hours. 25 ml of water and 75 ml of dichloromethane are subsequently added. The organic phase is separated by settling and is washed with 25 ml of water and then with 25 ml of a saturated aqueous sodium chloride solution. It is dried over magnesium sulphate and evaporated to dryness to produce 1.68 g of product in the form of an orange oil used directly in the following stage.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:20]([O:1][C:2]1[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:6][N:7]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NCCN(C(=O)OC(C)(C)C)C1

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (1 g, 5 mmol) in DCM (15 mL) was added triethyloxonium tetrafluoroborate (2.9 g, 15 mmol). Stirred for 2 h and neutralized with sat. aq NaHCO3. Layers separated and aqueous layer extracted with DCM. Combined organic layers dried over Na2SO4, filtered, and concentrated to give the title compound, which was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21](O)=[O:22].[N:24]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]([N:32]1[CH2:33][CH2:34][CH:29]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:30][CH2:31]1)=[O:22]
Reactant: Cc1c(C(=O)O)c(C(F)(F)F)nn1-c1cccc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(C(F)(F)F)nn1-c1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
In analogy to the procedure described in Example 160E), 5-methyl-3-trifluoromethyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a yellow foam (88%). MS: 475.2 (MH+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:34]2[N:43]=[CH:42][C:41]3[C:36](=[C:37]([F:48])[CH:38]=[C:39]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:40]=3)[C:35]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:31]=[C:22]3[CH2:23][N:24]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=1)(=O)C.[OH-].[Li+].O>C(O)(C)C.C1COCC1.O>[C:44]([C:39]1[CH:40]=[C:41]2[C:36](=[C:37]([F:48])[CH:38]=1)[C:35](=[O:49])[N:34]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:31]=[C:22]5[CH2:23][N:24]([CH:27]6[CH2:30][O:29][CH2:28]6)[CH2:25][CH2:26][N:21]5[N:20]=4)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:43]=[CH:42]2)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
A mixture of 155d (117 mg, 0.175 mmol) and lithium hydroxide•water (73.5 mg, 1.75 mmol) in i-propanol/THF (1:1, 8 mL) and water (1 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (6 mL). It was then extracted with dichloromethane (3×50 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 155 (30 mg, 27%) as a yellow solid. MS-ESI: [M+H]+ 628.3. 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.79-7.77 (m, 1H), 7.61 (d, J=4.5 Hz, 1H), 6.04 (s, 1H), 7.61-7.60 (m, 1H), 4.61-4.59 (m, 2H), 4.50-4.45 (m, 4H), 4.01-3.99 (m, 2H), 3.78 (s, 3H), 3.69-3.65 (m, 1H), 3.54 (s, 2H), 2.79-2.76 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].IC.C([O:16][C:17]1[C:25]([CH3:26])=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:27])C1C=CC=CC=1.Cl>CN(C=O)C.O>[OH:16][C:17]1[C:25]([CH3:26])=[CH:24][C:20]([C:21]([O:23][CH3:1])=[O:22])=[CH:19][C:18]=1[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
K2CO3 (3.0 g, 21 mmol) followed by iodomethane (1.2 mL, 20 mmol) were added to a solution of 4-benzyloxy-3,5-dimethyl-benzoic acid (5.0 g, 20 mmol) in DMF (100 mL) and the mixture was stirred at room temperature for 6 h. The solution was diluted with water and was acidified with 1% aq. HCl. The mixture was extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was taken up in degassed 2-propanol (100 mL). Pd/C (10%, 500 mg) was added and the mixture was again degassed and was backfilled with Ar. The mixture was introduced to an atmosphere of H2 (balloon) and was stirred overnight. The solids were removed by filtration through Celite and the filtrate was concentrated in vacuo to provide methyl 4-hydroxy-3,5-dimethyl-benzoate (91%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.56 (s, 2H), 3.76 (s, 3H), 3.38 (s, 9H), 2.19 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13].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>CS(C)=O.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=1[NH:1][C:12]([C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:13]
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the 2-amino-4-bromoaniline (6.0 g, 32.1 mmol), Boc-Pro-OH (6.90 g, 32.1 mmol) and HATU (13.42 g, 35.3 mmol) in dry DMSO (160 mL) was treated with diisopropylethylamine (14.0 mL, 10.4 g, 80 mmol) followed by stirring at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (3×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a brown solid which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([O:19][CH3:20])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:14]3[CH:17]=[CH:18][C:11]([OH:10])=[CH:12][C:13]=3[O:19][CH3:20])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: COc1cc(O)ccc1C=O
Product: COc1cc(O)ccc1-c1nc2cc(Br)cnc2[nH]1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-hydroxy-2-methoxybenzaldehyde.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cr](O)(O)(=O)=O>CC(C)=O.S(=O)(=O)(O)O>[C:1]([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Yield: 10.7 %

Procedure:
21.5 g. (0.81 mole) of N-carbobenzyloxy-4-hydroxy-L-proline is oxidized in 1.2 liters of acetone with 83 ml. of 8 N chromic acid in sulfuric acid as described in J.A.C.S. 79, 189 (1957). In order to facilitate the subsequent filtration of chromium salts, 30 g. of Celite (diatomaceous earth) is added to the acetone solution before introduction of the oxidizing agent. An air stirrer is employed. The reaction mixture is filtered and the acetone filtrate is concentrated to approximately 300 ml. before diluting with 1 liter of chloroform. The solution is washed with 300 ml. of saturated sodium chloride (four times), dried (MgSO4), filtered and the solvent evaporated to give N-carbobenzyloxy-4-keto-L-proline (22.8 g.) which is crystallized from ether (50 ml.)-hexane (150 ml.) to obtain 17.2 g. (81%) of product, m.p. 99°-101°, [α]D26 +17° (c, 1% in chloroform).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:34][C:35]([C:37]2[C:42](=[O:43])[N:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[CH:40]=[CH:39][N:38]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:16]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:10]=12.[CH:51](=O)[CH3:52].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]2[C:11]3=[N:12][CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:34][C:35]([C:37]5[C:42](=[O:43])[N:41]([C:44]6[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=6)[CH:40]=[CH:39][N:38]=5)=[O:36])=[CH:3][C:2]=4[F:1])=[C:10]3[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:51][CH3:52])[CH2:21][CH2:20]3)=[N:16]2)=[CH:31][CH:30]=1
Reactant: CC=O
Reactant: COc1ccc(Cn2nc(CC3CCNCC3)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1CCC(Cc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-(4-(1-(4-methoxybenzyl)-3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide (17 mg, 0.025 mmol; prepared as in Example 152, Step B) was added to a small round bottom flask and dissolved in dry THF (1.5 mL). Acetaldehyde (5.56 mg, 0.126 mmol) and a drop of acetic acid (d 1.049) were added. The reaction mixture was stirred for 10 minutes under N2(g) at room temperature. NaBH(OAc)3 (53.5 mg, 0.252 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and DCM and extracted with a second portion of DCM (10 mL). The combined organics were dried over sodium sulfate and evaporated to afford desired product, used as crude in next step. Yield 18.6 mg, 90% purity by HPLC, 94%. LRMS (APCI pos) m/e 706.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)C(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)C(O)C(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of 2-hydroxy-3-methylbutanoic acid (120 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one (230 mg, 70%). LC/MS: m/z 421.3 (M+H)+ at 2.43 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.79 (d, J=7.2 Hz, 1H), 4.11 (dd, J=7.0, 5.9 Hz, 1H), 3.87 (m, 8H), 2.52 (s, 3H), 1.91 (m, 1H), 0.88 (dd, J=22.8, 6.7 Hz, 6H).
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][C:5]1[CH:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].[CH3:17]I>CS(C)=O.O>[CH3:17][S:2][C:1](=[S:3])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1
Reactant: CI
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSC(=S)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Under an atmosphere of nitrogen, carbon disulfide (0.73 ml, 12 mmol) was added to a solution of 3-aminobenzotrifluoride (1.50 g, 9.3 mmol) in DMSO (10 ml). Subsequently, sodium hydroxide (0.56 ml, solution in water, 20 mol/l, 11 mmol) was added, and the dark brown reaction mixture was stirred for 30 min (r.t.). Upon the addition of methyl iodide (730 ml, 12 mmol), the mixture turned yellow and was stirred overnight (r.t.). The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried (Na2SO4), and the solvent evaporated under reduced pressure. The title compound (1.65 g, 71%) was obtained by purification of the residue (silica gel, heptan/ethyl acetate=100:0-80:20).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:18]([C:14]1[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=1[CH3:17])(=[O:19])=[O:20])([CH2:5][OH:6])[CH3:7]
Reactant: CC(N)(CO)CO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(CO)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 17.3 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1,3-propanediol (1.86 g, 17.7 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.5 g, 5.89 mmol) and triethylamine (0.9 ml, 6 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.33 g, 17%) as a white solid. MS (ISP) 322.2 [(M−H)−]; mp 201° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:15](=[O:21])[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C@H:10]([CH3:22])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from Example 1, Step A (2.2 g, 7.33 mmol) in THF (30 mL) was added lithium hexamethyldisilazide (16.0 mL, 1M in THF, 16.0 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 min. Iodomethane (2.8 mL, 45.0 mmol) was then added. After stirring at −78° C. for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (30:70 hexanes/ethyl acetate) afforded the desired product (major diastereoisomer from the reaction).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#C>>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11]
Reactant: NC(=O)c1cccc(O)c1
Reactant: C#CCCCCCCCCCO
Product: C#CCCCCCCCCOc1cccc(C(N)=O)c1

Procedure:
Synthesised from 3-hydroxybenzenecarboxamide and 10-undecyn-1-ol according to Method C, scheme 3; mp 111-112° C., HPLC-MS (method 1): m/z 274 [M+H]+, Rt=4.61 min.