Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COC2(N)N(C(NC3C=CC4OC(CO)=CC=4C=3)=NC=C2F)O1.[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH:54]([CH3:56])[CH3:55])=[CH:49][CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[O:40][C:39]([C:41](OC)=[O:42])=[CH:38][C:37]=3[CH:45]=2)=[N:30][CH:31]=1.CC(C[AlH]CC(C)C)C>>[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH:54]([CH3:56])[CH3:55])=[CH:49][CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[O:40][C:39]([CH2:41][OH:42])=[CH:38][C:37]=3[CH:45]=2)=[N:30][CH:31]=1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(OC(C)C)cc4)n3)ccc2o1
Agent: CC(C)C[AlH]CC(C)C
Agent: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Product: CC(C)Oc1ccc(Nc2nc(Nc3ccc4oc(CO)cc4c3)ncc2F)cc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine was reduced with DIBALH to yield 5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.83 (d, 1H, J=3.3 Hz), 7.81 (s, 1H), 7.50 (d, 2H, J=9.0 Hz), 7.29 (d, 1H, J=9.0 Hz), 7.22 (dd, 1H, J=2.4 and 8.7 Hz), 6.84 (d, 2H, J=8.7 Hz), 6.56 (d, 1H, J=1.2 Hz), 4.64 (s, 2H), 4.56 (2q, 1H, J=5.7 Hz), 1.31 (d, 6H, J=6.0 Hz); 19F NMR (CD3OD): −47926; LCMS: ret. time: 21.03 min.; purity: 99%; MS (m/e): 409 (MH+).
Reaction SMILES: [CH:1]1([CH:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][O:18][C:19]=3[N:20]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:28].C(OCC)(=O)C>>[ClH:28].[CH:1]1([CH:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19]=3[N:20]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(Oc1ccc2c(n1)OCCNC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A mixture of the compound obtained in step 1 (0.47 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.31 g, 79%) as a white powder. 1H-NMR (DMSO-d6): δ0.85-1.30 (5H, m), 1.18 (3H, t, J=6.2 Hz), 1.45-1.85 (6H, m), 3.56 (2H, brs), 4.24-4.32 (4H, m), 4.84-5.00 (1H, m), 6.55 (1H, d, J=8.1 Hz), 7.75 (1H, d, J=8.1 Hz), 9.56 (2H, brs)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN(CCN(C)C)C.[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[CH2:36][C:35](=[O:37])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[O:32][C:31]=2[CH:42]=1>C1COCC1>[OH:37][C:35]1([CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:34]2[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=2[O:32][C:31]2[CH:42]=[C:27]([O:26][CH3:25])[CH:28]=[CH:29][C:30]=2[CH2:36]1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)Oc1ccccc1C(=O)C2
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
Anhydrous EtOAc (0.94 mL, 9.6 mmole) was added dropwise to a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 7 mL, 7 mmole) in dry THF (7 mL) in a flame-dried flask at −78° C. under argon. After 0.5 hr, TMEDA (2.4 mL, 16 mmole) was added. After another 5 min, a solution of 3-methoxydibenzo[b,f]oxepin-10-one (760 mg, 3.2 mmole) in THF (2 mL) was added dropwise over 3 min. Additional dry THF (0.4 mL) was used in transfer. The reaction was stirred at −78° C. to −40° C. for 1 hr, then was quenched with saturated NH4Cl (10 mL). The mixture was wanned to RT and extracted with EtOAc. Drying (MgSO4), concentration, and flash chromatography on silica gel (10% EtOAc/hexanes) gave the title compound as a clear oil: 1H NMR (300 MHz, CDCl3) δ1.14-1.20 (t, 3 H), 1.21-1.30 (m, 1 H), 2.62-2.68 (dd, 1 H), 2.94-3.02 (dd, 1 H), 3.24-3.30 (dd, 1 H), 3.40-3.46 (dd, 1 H), 3.40-3.46 (dd, 1 H), 3.78 (s, 3 H), 4.08-4.18 (m, 2 H), 6.60-7.26 (m, 6 H), 7.64-7.68 (dd, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[Si:25]([O:42][CH2:43][CH2:44][C@@H:45](O)[CH3:46])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[Si:25]([O:42][CH2:43][CH2:44][C@H:45]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:2]([F:1])[CH:3]=1)[CH3:46])([C:38]([CH3:39])([CH3:40])[CH3:41])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Reactant: C[C@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a tetrahydrofuran solution (24 ml) of benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (Example 1-3) (968 mg) were added at room temperature (2S)-4-{[tert-butyl(diphenyl)silyl]oxy}butan-2-ol (1.48 g), triphenylphosphine (1.18 g) and di-tert-butyl azodicarboxylate (1.04 g), followed by stirring overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford benzyl 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-carboxylate (2.25 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17](OCCCC)=[O:18])[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2].[NH3:26]>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:26])=[O:18])[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2]
Reactant: N
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3CC)C(=O)O1
Solvent: CO
Product: CCn1c(=O)sc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 3, 500 mg, 1.37 mmol) is treated with 7N ammonia in MeOH (14 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) and stirred at ambient temperature for 30 mins. The resulting slurry is filtered to give the title compound, mp 211-212.5° C.; MS (ESI+) for C13H13N3O4S m/z 308 (M+H)+; [α]25D−25 (c 0.92, DMSO).
Reaction SMILES: C([O:4][C:5]1[C:28]([Cl:29])=[CH:27][C:8]([C:9]([NH:11][CH:12]2[C:18](=[O:19])[N:17]([CH:20](C)[C:21](O)=O)[N:16]([CH3:25])[C:15](=[O:26])[CH2:14][CH2:13]2)=[O:10])=[CH:7][C:6]=1[Cl:30])C=C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(O[C:49](=[O:65])[NH:50][CH:51]1[CH2:55][C:54](=[O:56])[O:53][CH:52]1[O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:58]([O:57][CH:52]1[CH:51]([NH:50][C:49]([CH:20]([N:17]2[C:18](=[O:19])[CH:12]([NH:11][C:9](=[O:10])[C:8]3[CH:27]=[C:28]([Cl:29])[C:5]([OH:4])=[C:6]([Cl:30])[CH:7]=3)[CH2:13][CH2:14][C:15](=[O:26])[N:16]2[CH3:25])[CH3:21])=[O:65])[CH2:55][C:54](=[O:56])[O:53]1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(C)N(C(C)C(=O)O)C2=O)cc1Cl
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C(=O)NC1CC(=O)OC1OCc1ccccc1)N1C(=O)C(NC(=O)c2cc(Cl)c(O)c(Cl)c2)CCC(=O)N1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
To a solution of 2-[6-(4-allyloxy-3,5-dichloro-benzoylamino)-2-methyl-3,7-dioxo-[1,2]diazepan-1-yl]-propionic acid (18) (183 mg, 0.40 mmol) in dichloromethane was added HOBT (65 mg, 0.48 mmol) followed by EDC (123 mg, 0.64 mmol). The mixture was stirred at 0° C. for 30 min, then a solution of (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (9, anti diastereomer) (140 mg, 0.48 mmol) in dichloromethane, charged with 1,3-dimethylbarbituric acid (DMBA) (75 mg, 0.48 mmol) and Pd(PPh3)4 (60 mg, 0.05 mmol) for 30 min, was added and the resulting mixture was stirred at room temperature for 5 hours. The second portion of DMBA (63 mg, 0.40 mmol) was added and the reaction mixture was continuously stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a pale yellow solid, that was purified by flash chromatography using dichloromethane/methanol (99/1 to 95/5) to afford 70 mg (29% yield) of the title compound as a mixture of diastereomers. 1H-NMR (500 MHz, CDCl3) δ 1.39-1.45 (m, 3H), 2.60-2.80 (m, 2H), 2.80-3.10 (m, 1H), 3.12-3.32 (m, 4H), 4.20-4.62 (m, 2H), 4.70-4.88 (m, 2H), 5.25-5.45 (m, 1H), 6.65-6.95 (m, 3H), 7.20-7.50 (m, 5H), 7.61 (s, 1H), 7.72 (d, 1H). Analytical HPLC: 10.86 and 10.98 min. LC-MS (ES+): m/e=607, 609 (M+H+).
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cnc(Br)o1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2ccccc2Cl)o1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
Under argon, 300 mg (1.71 mmol) of ethyl 2-bromo-1,3-oxazole-5-carboxylate together with 422 mg (2.56 mmol) of 2-chlorophenylboronic acid were dissolved in 7 ml of toluene, and 67 mg (0.17 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 78 mg (0.085 mmol) of tris(dibenzylideneacetone)dipalladium and 725 mg (3.42 mmol) of potassium phosphate were added successively. The mixture was heated to 110° C. and stirred at this temperature for 20 h. For work-up, the reaction mixture was allowed to cool to RT and diluted with 20 ml of ethyl acetate and 20 ml of water. After phase separation, the aqueous phase was extracted two more times with in each case 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [Method 19]. This gave 217 mg (50% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[S:8])=[O:5].C1(C)C=CC=CC=1>O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]2[S:8][C:2]3[N:20]=[CH:19][CH:18]=[CH:17][C:3]=3[C:4](=[O:5])[N:6]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(NC(=S)NC(=O)c2cccnc2Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Yield: 94.1 %

Procedure:
5.66 g of 1-(2-chloronicotinoyl)-3-(4-methylphenyl)thiourea and 30 mf of toluene were put in a 100 ml flask. To the flask were then connected a Dean-Stark water separator and a Dimroth condenser. The mixture was then heated under reflux for 4 hours. The reaction mixture was then allowed to cool. The resulting precipitate was collected by filtration, washed with toluene, and then dried under reduced pressure to obtain 4.69 g of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [OH-].[K+].[C:3]([CH:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:6][C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])#[N:4].N.[H][H]>CO.[Ni]>[NH2:4][CH2:3][CH:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:6][C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8]
Reactant: CCN(CC)C(=O)CC(C#N)CC(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Agent: [K+]
Solvent: CO
Product: CCN(CC)C(=O)CC(CN)CC(C)C
Temperature: 30 °C
Reaction time: 22 h

Procedure:
To a solution of potassium hydroxide (19 grams) in methanol (114 ml), 3-cyano-N,N-diethyl-5-methyl hexanamide (9.5 grams) was added followed by ammonia solution (38 ml) and Raney nickel (19 grams). Hydrogen pressure of 4.0 kg/cm2 was applied and the reaction mixture was stirred at 30° C. for 22 hours. The reaction mixture was filtered through a hyflow bed. The solvent was distilled off under reduced pressure at a temperature below 60° C. Water (200 ml) was added to the reaction mixture and pH adjusted to 2 with concentrated hydrochloric acid. The aqueous layer was extracted with dichloromethane. The pH of aqueous layer was adjusted to 8.0, with 50% sodium hydroxide. The aqueous layer was extracted with dichloromethane. The solvent was distilled off completely under atmospheric pressure to obtain the title compound as a residue.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl.N1C=CC=CC=1>>[NH:16]1[CH2:17][CH2:18][CH:13]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:11])([F:12])[F:10])[C:3]=2[OH:2])[CH2:14][CH2:15]1
Reactant: COc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: Oc1c(C2CCNCC2)cccc1C(F)(F)F

Procedure:
Preparation according to Example 29: 4-[2-methoxy-3-(trifluoromethyl)phenyl]piperidine (0.07 g, 0.27 mmol), pyridine hydrochloride (0.4 g). Yield: 0.05 g. MS m/z (relative intensity, 70 eV) 245 (M+, bp), 226 (21), 167 (25), 140 (15), 56 (42).
Reaction SMILES: [Cl-].O[NH3+].[CH3:4][O:5][C:6]1[CH:47]=[CH:46][C:9]([CH2:10][N:11]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]3[C:20]([NH:27][C:28]4[CH:29]=[N:30][C:31]([O:35][CH3:36])=[C:32]([F:34])[CH:33]=4)=[N:21][CH:22]=[C:23]([CH:26]=3)[CH:24]=O)[N:13]=2)=[CH:8][CH:7]=1.[N:48]1C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C=O)C.CO.O>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:47][CH:46]=2)[C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]3[C:20]([NH:27][C:28]4[CH:29]=[N:30][C:31]([O:35][CH3:36])=[C:32]([F:34])[CH:33]=4)=[N:21][CH:22]=[C:23]([CH:26]=3)[C:24]#[N:48])[N:13]=2)=[CH:43][CH:42]=1
Reactant: c1ccncc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C#N)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A dark brown solution of hydroxyammonium chloride (0.700 g, 10.07 mmol), 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 143, 2.00 g, 3.36 mmol) and pyridine (0.815 mL, 10.07 mmol) in 15 mL DMF was allowed to stir 2 h. The reaction was partitioned between water and EtOAc. The organic layer was washed with water 2 times, saturated aqueous NaCl once, and the organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an orange solid, 2.0 g. This was treated with acetic anhydride (15.84 mL, 168 mmol), and the flask fitted with a water-cooled reflux condenser, and placed in an oil bath. The reaction was heated to reflux for 5 h, and then the reaction was cooled and stirred overnight. The slurry was treated with 80 mL MeOH, filtered and dried in vacuo to give 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinonitrile (1.50 g, 2.53 mmol, 75% yield) as a green-brown solid. m/z (ESI, +ve ion) 593 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 12.46 (s, 1H), 8.99 (d, J=2.3 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.3 Hz, 1H), 7.92 (dd, J=11.7, 2.2 Hz, 1H), 7.12-7.25 (m, 4H), 6.82-6.94 (m, 4H), 4.88 (s, 2H), 4.82 (s, 2H), 4.04 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:14]=1)[C:9]([NH2:11])=O)([CH3:5])[CH3:4])#[N:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:14]=1)[C:9]#[N:11])([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(N)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C#N)c1cc(C#N)cc(Cn2cncn2)c1
Reaction time: 18 h

Procedure:
A mixture of the product from Example 22 (0.41 g), pyridine (0.25 ml) and 1,4-dioxan (5 ml) was stirred while trifluoroacetic anhydride (0.24 ml) was added dropwise The resulting solution was kept at room temperature for 18 h, diluted with water (10 ml), made basic with sodium hydrogen carbonate and extracted three times with ethyl acetate. The extracts were combined, dried and evaporated to dryness, and the residue was purified by flash column chromatography, eluting with methanol:chloroform (3:97 by volume) to give 3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)benzonitrile, mp. 90°-92°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][NH:6][CH:7]=[O:8])[CH3:2].CN1C=CN=C1.[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.C(Cl)Cl>[CH:7]([NH:6][CH:5]([C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CNC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCC(=O)C(NC=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
A methylene chloride solution (100 ml) of N-formylglycine ethyl ester (1.31 g, 10 mmol) and N-methylimidazole (985.4 mg, 12 mmol) was cooled to −45° C., and a methylene chloride solution (10 ml) of palmitoyl chloride (2.85 mg, 10 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, a methylene chloride solution (10 ml) of titanium tetrachloride (6.78 mg, 35 mmol) and a methylene chloride solution (10 ml) of tributylamine (7.42 g, 40 mmol) were added thereto. The resulting mixture was stirred for 3 hours at −45° C. After 100 ml of water was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. Further, the water layer was extracted twice with methylene chloride. The organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, solely ethyl acetate) to obtain the title compound (3.15 mg, yield: 85%).
Reaction SMILES: [C:1]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH:11]1[CH2:14][CH:13]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]3[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][C:27]=3[F:39])=[N:17]2)[CH2:12]1.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH2:15][CH:13]3[CH2:14][N:11]([C:4]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:1]#[N:2])=[O:6])[CH2:12]3)[N:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:28][C:27]=3[F:39])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CNC1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CC(Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid (48.12 mg, 0.350 mmol), 1-(azetidin-3-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.230 mmol) in DCM (2 mL) was added PyAOP (134.9 mg, 0.250 mmol) and TEA (0.1 mL, 0.690 mmol) and the resulting yellow solution stirred at rt for 1 h. LCMS showed that the reaction was completed and the crude mixture was directly loaded onto a silica gel cartridge for purification (0.2 to 3% MeOH: CH2Cl2). Removal of solvent from cleanest fractions afforded 2-[3-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (12 mg LCMS. (M+1=512).
Reaction SMILES: O[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:4]1[N:5]([CH2:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:7][CH:8]=1)[CH3:3].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>>[CH3:12][O:11][CH2:10][CH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:21])=[O:22])=[CH:15][CH:14]=1)[CH3:3]
Reactant: COCCn1cccc1C(C)(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Product: COCCn1cccc1C(C)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from N-(4-{1-hydroxy-1-[1-(2-methox-yethyl)-1H-pyrrol-2-yl]-ethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 1) using triethylsilane and boron trifluoride diethyl etherate as described in Example 88 of U.S. application Ser. No. 10/354,922, now U.S. Pat. No. 7,071,358, and provided below as Preparative Example B.
Reaction SMILES: ClCS([O:6][C:7]1[C:8]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:24])=[N:9][C:10]([C:14]([NH:17][S:18]([CH2:21]Cl)(=[O:20])=[O:19])([CH3:16])[CH3:15])=[N:11][C:12]=1[OH:13])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23]([C:8]2[N:9]=[C:10]3[N:11]([C:12](=[O:13])[C:7]=2[OH:6])[CH2:21][S:18](=[O:19])(=[O:20])[NH:17][C:14]3([CH3:16])[CH3:15])=[O:24])=[CH:32][CH:31]=1
Reactant: CC(C)(NS(=O)(=O)CCl)c1nc(O)c(OS(=O)(=O)CCl)c(C(=O)NCc2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)NS(=O)(=O)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Crude chloride of Step 1 was dissolved in 1,4-dioxane and Cs2CO3 (2 eq.) was added. The reaction mixture was stirred at 100° C. overnight, then cooled down to room temperature, taken up in EtOAc washed with brine, dried over Na2SO4. The solvent was removed under reduced pressure and the resulting brown oil was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant). Lyophilization of appropriate fractions gave title compound as a white solid.