Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:28])([F:27])[O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.CCOC(C)=O>CCOCC>[F:7][C:8]([F:27])([F:28])[O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Cc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCc1ccc(Cc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
LiAlH4 (55 mg, 1.45 mmol) was added to a solution of ester 94 (203 mg, 0.65 mmol) in ether (5 mL) and the mixture was stirred at room temperature for 3 h, then EtOAc (150 mL) was added. The organic layer was washed with water, the aqueous layer was re-extracted with EtOAc (100 mL), and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give {4-[4-(trifluoromethoxy)benzyl]phenyl}methanol (95) (185 mg, quant.) as a white solid: mp (EtOAc/hexane) 60-61° C.; 1H NMR (CDCl3) δ 7.32-7.27 (m, 2H), 7.20-7.14 (m, 4H), 7.13-7.09 (m, 2H), 4.67 (s, 2H), 3.98 (s, 2H); HREIMS calcd for C15H13F3O2 m/z (M+) 282.0868, found 282.0866.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][CH:5]([CH2:13]O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][CH2:2][C@@H:3]([O:15][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:4][C:5](=[CH2:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C(CO)C[C@H](O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C[C@@H](CCl)OS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
To a stirred solution of tert-butyl (4S)-5-chloro-4-hydroxy-2-hydroxymethylpentanoate (10.0 g) and triethylamine (12.7 g) in methylene chloride (100 ml), mesyl chloride (11.5 g) was added dropwise under ice-cooling and the mixture was stirred for 20 minutes. The mixture was concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was dissolved in benzene (130 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.0 g) was added to the solution. The mixture was stirred for 2 hours at room temperature. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 11.1 g (89%) of tert-butyl (4S)-5-chloro-4-mesyloxy-2-methylenepentanoate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]([C:39]2[N:40]=[N:41][NH:42][N:43]=2)[CH:36]=[CH:37][CH:38]=1.[Si:44]([O:51][CH2:52][CH2:53][CH:54](O)[CH3:55])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C1COCC1>[Si:44]([O:51][CH2:52][CH2:53][CH:54]([N:41]1[N:42]=[N:43][C:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=2)=[N:40]1)[CH3:55])([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:45])[CH3:46]
Reactant: CC(O)CCO[Si](C)(C)C(C)(C)C
Reactant: Clc1cccc(-c2nn[nH]n2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCO[Si](C)(C)C(C)(C)C)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 98.1 %

Procedure:
To triphenylphosphine (2.6 g, 10 mmol) in THF (50 mL) at 0° C. under argon, DEAD (1.6 mL, 10 mmol) added during 5 minutes. After stirring for 40 minutes at 0° C. 5-(3-chlorophenyl)-2H-tetrazole (0.90 g, 5 mmol) followed by a solution of 4-{[tert-butyl(dimethyl)silyl]oxy}butan-2-ol (1.53 g, 7.5 mmol) (Tett. 2003, 59, 4739-4748) in THF (5 mL) was added. Stirring at 0° C. for 10 minutes was followed by 21 h at r.t. The mixture was concentrated and purified by flash column chromatography (SiO2, Heptane-EtOAc 7:1) to give 1.8 g (98%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1)[CH:2]=[CH2:3]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: C=CCOc1ccccc1OCC1CO1
Solvent: CCO
Product: C=CCOc1ccccc1OCC(O)CN1CCC(N2CCCNC2=O)CC1

Procedure:
A solution of 10.3 g of 1-(o-allyloxy-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml abs. ethanol is heated for 5 hours to 95°C and then evaporated in vacuo. The residue is recrystallised from isopropanol to yield the 1-[3-(o-allyloxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)piperidine, which melts at 122°-125°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:30][NH2:31]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([NH:30][NH2:31])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NN
Temperature: 70 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (0.061 g, 2.16 mmol) was dissolved in THF (5 mL) then 1,1′-carbonyldiimidazole (0.390 g, 2.38 mmol) was added and the reaction was heated to 70° C. for 40 minutes. The reaction was then cooled to 0° C. and hydrazine monohydrate (0.220 mL, 4.32 mmol) was added. The reaction was then allowed to slowly warm to room temperature and stirred overnight. Standard aqueous workup afforded the title compound, which was brought to the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[ClH:23].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH2:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: NNC1CCNCC1
Temperature: 90 °C

Procedure:
A mixture of 0.1 mole of 4-(N′-tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (compound 5f) and 150 ml of concentrated hydrochloric acid is heated at 90° C. for 60 min after which the clear solution is evaporated. The residue is washed with tetrahydrofurane, filtered off and dried under vacuum. M. p. 256-259° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:39][OH:40]>O1CCCC1>[OH:40][NH:39][C:13](=[O:14])[CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:25]
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2Cc3ccccc3C2=O)cc1OC
Yield: 78.3 %

Procedure:
N-Hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (5.00 g, 14.7 mmol), carbonyldiimidazole (2.49 g, 15.4 mmol) and hydroxylamine hydrochloride (1.30 g, 19.1 mmol) in tetrahydrofuran (15 mL) to afford N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide as a white solid (4.1 g, 79% yield): mp, 188.5-189.5° C.; 1H NMR (DMSO-d6) δ2.82-2.87 (m, 2H, CH2), 3.71 (s, 3H, CH3), 3.74 (s, 3H, CH3), 4.15 (d, J=17.5 Hz, NCHH), 4.63 (d, J=17.5 Hz, 1H, NCHH), 5.74 (t, J=7.7 Hz, 1H, NCH), 6.85-6.93 (m, 3H, Ar), 7.45-7.69 (m, 4H, Ar), 8.83 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ35.11, 46.26, 51.25, 55.50, 111.09, 111.76, 119.19, 122.79, 123.43, 127.84, 131.29, 131.91, 132.27, 141.68, 148.27, 148.69, 166.03, 166.84; Anal Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 64.08; H, 5.55; N, 7.86.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1.[OH-].[Na+].C(OC([O-])=O)(=O)[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>O1CCOCC1>[NH:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1
Reactant: N#Cc1cccc(C[C@H](N)C(=O)O)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2.5 g (13.1 mmol) of H-Phe(3-CN)—OH were dissolved in 100 ml of dioxane and, at 0° C., 13 ml (13 mmol) of 1N NaOH and 3.16 g (14.5 mmol) of Boc pyrocarbonate were added. The mixture was stirred at 0° C. for 20 min and then at room temperature for 4 h, during which a total of 7 ml (7 mmol) of 1N NaOH was added in portions, thus keeping the pH constant at 8-8.5. The solvent was removed in vacuo, and the residue was taken up in ethyl acetate, washed in each case 3× with 5% KHSO4 and 3× with NaCl-saturated water and then dried over Na2SO4. The solvent was removed in vacuo. A white solid was obtained as residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Cl[C:13]([F:19])([F:18])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:18][CH:13]([F:19])[O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1OC(F)F
Temperature: 120 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
5-Bromo-2-nitrophenol (1 g, 4.59 mmol) and methyl 2-chloro-2,2-difluoroacetate (991 mg, 6.9 mmol) were dissolved in dry DMF (3 mL). Potassium carbonate (1.27 g, 9.18 mmol) was added and the reaction was stirred at 120° C. for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20% dichloromethane in hexanes to afford the title compound as a dark brown oil (375 mg, 30%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:36])=[C:18]([C:20]2[C:21](=[O:35])[NH:22][C:23]3([C:33]=2[OH:34])[CH2:32][CH2:31][C:26]2(OCC[O:27]2)[CH2:25][CH2:24]3)[CH:19]=1>CC(C)=O.O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:36])=[C:18]([C:20]2[C:21](=[O:35])[NH:22][C:23]3([CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32]3)[C:33]=2[OH:34])[CH:19]=1
Reactant: Cc1ccc(Br)cc1C1=C(O)C2(CCC3(CC2)OCCO3)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(Br)cc1C1=C(O)C2(CCC(=O)CC2)NC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
192 mg (1.01 mmol) of 4-toluenesulphonic acid monohydrate were added to 2.49 g (6.32 mmol) of 11-(5-bromo-2-methylphenyl)-12-hydroxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-en-10-one (Example 38A) in 26 ml of acetone and 13 ml of water. The reaction mixture was stirred at 80° C. overnight. For work-up, the cold reaction mixture was diluted with water and acetone was removed on a rotary evaporator. The precipitated crude product was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. Drying gave 1.97 g (89% of theory) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:3])=[O:2].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[C:32]2[S:26][C:27](=[S:28])[NH:29][C:30]2=[O:31])=[CH:20][CH:21]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(OCc2ccccc2-c2ccccc2C(=O)O)cc1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccccc2-c2ccccc2C(=O)O)cc1
Yield: 79085.6 %

Procedure:
The 4-[2-(2-carboxyphenyl)benzoxy]benzaldehyde (93.7 mg, 0.28 mmol) was then coupled with rhodanine (37.5 mg, 0.28 mmol) as described supra to yield the title product (99.1 g, 79%). mp >225° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[S:14]
Reactant: NC(=O)Cc1cccc(Cl)c1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: NC(=S)Cc1cccc(Cl)c1Cl
Temperature: 90 °C
Yield: 72.7 %

Procedure:
A solution of (2,3-dichloro-phenyl)-acetamide (4.50 g, 22 mmol,) in toluene (50 ml) was treated at r.t. with P2S5 (9.80 g, 22 mmol). The reaction mixture was heated to 90° C. for 1.5 h, cooled to r.t., and filtered. The solid was washed with ether and the washings were combined with the filtrate. The combined solutions were extracted twice with 10% aq. NaOH. The combined aqueous extracts were acidified at 0° C. with HCl. The precipitate was collected and recrystallized from ethyl acetate/hexane to afford (2,3-dichloro-phenyl)-thioacetamide (3.40 g, 16 mmol). HPLC Rt: 5.91 min. 1H-NMR (CDCl3): δ 8.80 (br. s, 1H, NH), 8.5 (d, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 2.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36]O)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:26]CC5C=CC=CC=5)[CH:14]=[CH:15][C:16]=4[O:18]CC4C=CC=CC=4)[C:11](=[O:34])[C:10]=1[C:9]=23.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:49]1[CH:54]=[CH:53]C=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][N:49]([CH2:54][CH3:53])[CH2:50][CH3:51])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([OH:26])[CH:14]=[CH:15][C:16]=4[OH:18])[C:11](=[O:34])[C:10]=1[C:9]=23
Reactant: c1ccncc1
Reactant: O=C1c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2-c2nn(CCO)c3ccc(Cl)c1c23
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCN(CC)CCn1nc2c3c(c(Cl)ccc31)C(=O)c1c(O)ccc(O)c1-2
Temperature: 0 °C
Reaction time: 50 h

Procedure:
An ice-cold mixture of 22 g (43 mmol) of 5-chloro-2-(2-hydroxyethyl)-7,10-bis(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one, 12.3 g (65 mmol) of p-toluenesulfonyl chloride and 170 ml of pyridine is stirred for 50 hours. The solid is filtered, washed with methanol and diethyl ether, and dried to give 10.5 g of the product; mp 203°-206° C. (decomposition). Processing of the filtrate gives 9.3 g of additional product; mp 182°-188° C. (decomposition).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:6][NH:5][C@H:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])=[N:9]2)[CH2:3]1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C@@H:4]3[CH2:3][C:2]([F:1])([F:32])[CH2:6][N:5]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])[C:11]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@@H]1CC(F)(F)CN1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: N#CCC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 1-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (850 mg, crude), 2-cyanoacetic acid (120 mg, 1.31 mmol, 1.29 equiv) and TEA (650 mg, 6.45 mmol, 5.00 equiv) in dichloromethane (30 mL), was added HATU (500 mg, 1.32 mmol, 1.29 equiv). The resulting solution was stirred at room temperature overnight. The mixture was diluted with DCM, washed with HCl (2N), sat. NaHCO3, brine, dried over sodium sulfate and concentrated. The residue was submitted to chromatography (SiO2, DCM: MeOH=30:1) to give 0.4 g (77%) of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidin-1-yl]-3-oxopropanenitrile as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:15][O:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C=O)ccc([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 2-hydroxy-3-methoxy-4-nitro-benzaldehyde (10.4 g, 52.8 mmol, prepared as described in: J. Heterocyclic Chem., 1996, 33, 1171-78) in DMF (100 ml) was added potassium carbonate (11.04 g, 80 mmol), followed by methyl iodide (4 mL, 64 mmol) and the mixture stirred at 90° C. for 1 hour. The mixture was partitioned between ethyl acetate and water, separated, the organic phase was washed with brine, dried (Na2SO4), filtered, and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a yellow oil (8.2 g, 74%). LCMS (Method B): RT=3.76 min, [M+H]+=212.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][C@H:35]([CH3:39])[NH:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:36][C@H:35]([CH3:39])[NH:34][C@H:33]([CH3:32])[CH2:38]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:31])[F:29])[CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: C[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@H](C)N1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((3R,5S)-3,5-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R,6S) 2,6-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1cccc(-c2cc(Br)ccn2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5cccc(F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-(3-fluoro-phenyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:3][CH:4]=3)[NH:9][C:10]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a suspension of 2-(4-aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (80 mg, 0.24 mmol) [See Ex. 28 above] and triethylamine (0.12 mL, 0.86 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (55 mL, 0.72 mmol). After stirring at rt for 1 h, the mixture was poured into aqueous NaHCO3 and extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 2-10% MeOH/CHCl3 to afford the title compound as a tan solid (35 mg, 36%): ESMS (m/z): 409 (M+ +H).
Reaction SMILES: [CH2:1]([O:19][C:20](=[O:43])[CH:21]([NH:32]C(OCC1C=CC=CC=1)=O)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:19][C:20](=[O:43])[CH:21]([NH2:32])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(N)Cc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
2-Benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid Stearyl Ester (430 g) was dissolved in ethyl acetate (2500 ml) in a pressure vessel. 10% Palladium carbon (58 g, 50% wet) was added and the reaction mixture was stirred under an atmosphere of Hydrogen (10 Kg) at 50° C. for 12 hours. The reaction mixture was brought to 20° C. and the catalyst was removed by filtration. The solvent was distilled off and the resulting diamine was precipitated by adding hexane. It was filtered and dried to yield pure 2-amino-3-(4-amino -phenyl)-propionic acid octadecyl ester (200 g) as a white powder with a melting point of 54-56° C. and a purity of 98% as determined by HPLC. The product was further characterized by IH NMR (CDCl3) δ 0.90 (t, 3H, CH3), 1.25 (m, 30H, 15X CH2), 1.65 (m, 2H, CH2), 2.90-3.05 (m, 2H, CH2), 3.70 (m, 1H, CH), 4.00-4.15 (m, 6H, 2X NH2 & CH2), 6.60 (d, 2H, Ar), 6.95 (d, 2H, Ar)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cccnc1NCc1ccccc1
Yield: 91 %

Procedure:
In accordance with the same procedures as in Step 1 of Preparation 4, except for using 2-chloro-3-nitropyridine and benzylamine, the titled compound was obtained as yellow solid. (Yield: 91%)