Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:17][C:12]1[CH:11]=[C:10]([N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[C:28]2[CH:29]=[CH:30][C:25]([C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)=[CH:26][CH:27]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Ic1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(Nc2ccc(C)c(C)c2)cc1C
Agent: [K+]
Agent: [OH-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
In a 500 milliliter round bottomed flask equipped with mechanical stirrer and fitted with a Dean-Stark trap under a reflux condenser were placed 12.39 grams (0.055 mole) of bis(3,4-dimethylphenyl)amine, 14 grams (0.050 mole) of 4-iodobiphenyl, 0.25 gram (0.0025 mole) of cuprous chloride, 0.45 gram (0,0025 mole) of 1,10-phenanthroline, 22.44 grams (0.4 mole) of flake potassium hydroxide and 20 milliliters of toluene solvent. The reaction was heated quickly to a reflux temperature of 120° C. and maintained at this temperature for 4 hours after which time chromatographic analysis revealed the reaction to be complete. The reaction was cooled to room temperature, about 25° C., and partitioned between 200 milliliters of toluene and 150 milliliters of deionized water. The resulting organic layer was separated and water removed by azeotropic distillation of the solvent under a Dean-Stark trap. The product was decolorized by slurry treating the toluene solution with 10 grams of Filtrol-24™, an acid washed clay, and 10 grams of Alcoa CG-20 alumina. After 3 hours stirring at reflux, the solution was hot filtered to remove the clay and alumina, and cooled to room temperature. Evaporation of the solvent and recrystallization from octane provided the above product compound in a yield of 10.2 grams (76 percent) and which product melted at 113.8° C. This product of N,N-bis(3,4-dimethylphenyl)-4-biphenylamine was suitable for further purification by conventional means to afford electronic grade, about 99 percent pure, product. The above total reaction time was an accelerated 4 hours.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:30][CH:12]2[N:13]([N:20]=[CH:21][CH:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[OH:23])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][CH3:18])[CH:11]2[CH2:10]1)=[O:4].[OH-].[Li+].Cl.O>CO.O>[C:3]([CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:30][CH:12]2[N:13]([N:20]=[CH:21][CH:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[OH:23])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][CH3:18])[CH:11]2[CH2:10]1)([OH:4])=[O:2]
Reactant: CCCN1C(=O)N(N=CC(O)C2CCCCC2)C2CC(SCCCC(=O)OC)CC21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN1C(=O)N(N=CC(O)C2CCCCC2)C2CC(SCCCC(=O)O)CC21
Temperature: 45 °C
Yield: 84.9 %

Procedure:
The compound of Example 1 (1.4 g) was dissolved in methanol:water (2:1, 10 ml) and to the stirred solution was added lithium hydroxide (0.267 g). The resulting mixture was maintained at 45° C. for one hour. The pH was adjusted to 5.0 with 2N HCl, water (50 ml) was added and the product was extracted into chloroform (50 ml). After drying over anhy. sodium sulphate, the mixture was filtered and the filtrate concentrated in vacuo to give the desired product (1.15 g).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)(Cl)Cl>[F:1][CH2:2][C:3]1[CH2:4][S:5](=[O:45])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CF)=CS[C@H]12
Solvent: ClC(Cl)Cl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS(=O)[C@H]12
Reaction time: 2.5 h

Procedure:
To a solution of 1.04 g of benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate in 10 ml of CHCl3 at 0° is added dropwise a solution of 0.35 g of m-chloroperbenzoic acid in 5 ml of CHCl3. The solution is stirred at 0° for 2.5 hours, then diluted with CHCl3 and washed with NaHCO 3, the dried (MgSO4) and evaporated in vacuo. The residue is recrystallized from methanol to yield benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC(O[N:78]2[C:82](=[O:83])[CH2:81][CH2:80][C:79]2=[O:84])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:86].[Na+].[Na+].[Na+].[Na+].[C:91]([CH2:94][CH2:95][C:96]1[CH:97]=[C:98](/[C:102](=[CH:136]\[CH:137]=[C:138]2\[N:139]([CH2:161][CH2:162][CH2:163][CH2:164][S:165]([O-:168])(=[O:167])=[O:166])[C:140]3[CH:141]=[CH:142][C:143]4[C:152]([S:153]([O-:156])(=[O:155])=[O:154])=[CH:151][C:150]([S:157]([O-:160])(=[O:159])=[O:158])=[CH:149][C:144]=4[C:145]=3[C:146]\2([CH3:148])[CH3:147])/[CH:103]=[CH:104]/[C:105]2[C:113]([CH3:115])([CH3:114])[C:112]3[C:111]4[CH:116]=[C:117]([S:124]([O-:127])(=[O:126])=[O:125])[CH:118]=[C:119]([S:120]([O-:123])(=[O:122])=[O:121])[C:110]=4[CH:109]=[CH:108][C:107]=3[N+:106]=2[CH2:128][CH2:129][CH2:130][CH2:131][S:132]([O-:135])(=[O:134])=[O:133])[CH:99]=[CH:100][CH:101]=1)([OH:93])=[O:92].[Na+].[Na+].[Na+].[Na+].[Na+]>>[CH3:114][C:113]1([CH3:115])[C:112]2[C:111]3[CH:116]=[C:117]([S:124]([O-:127])(=[O:125])=[O:126])[CH:118]=[C:119]([S:120]([O-:123])(=[O:121])=[O:122])[C:110]=3[CH:109]=[CH:108][C:107]=2[N:106]([CH2:128][CH2:129][CH2:130][CH2:131][S:132]([O-:135])(=[O:134])=[O:133])/[C:105]/1=[CH:104]/[CH:103]=[C:102](\[C:98]1[CH:99]=[CH:100][CH:101]=[C:96]([CH2:95][CH2:94][C:91]([O:93][N:78]2[C:82](=[O:83])[CH2:81][CH2:80][C:79]2=[O:84])=[O:92])[CH:97]=1)/[CH:136]=[CH:137]/[C:138]1[C:146]([CH3:148])([CH3:147])[C:145]2[C:144]3[CH:149]=[C:150]([S:157]([O-:160])(=[O:158])=[O:159])[CH:151]=[C:152]([S:153]([O-:156])(=[O:154])=[O:155])[C:143]=3[CH:142]=[CH:141][C:140]=2[N+:139]=1[CH2:161][CH2:162][CH2:163][CH2:164][S:165]([O-:168])(=[O:167])=[O:166].[Na+:86].[Na+:86].[Na+:86].[Na+:86].[Na+:86]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 11 was prepared analogously to compound 9 (Example 9), except that compound 10 was used as a starting material.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]C(=O)C)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C[O-].[Na+]>O1CCCC1.CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][SH:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(=O)SCc1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(CS)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.35-A of Step 1 (160 mg, 0.49 mmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was cooled to 0° C. and degassed. The reaction mixture was treated with sodium methoxide (0.30 mL, 3.3 mmol, 25 wt % solution in methanol) dropwise and stirred at 0° C. for 5 min. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (10 mL), dried with sodium sulfate, filtered, and concentrated to give a white solid which was used in the next step without further purification. LCMS found for C14H15O2S2 (M+H)+: m/z=279.
Reaction SMILES: [C:1]([CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:6])(O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:54]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])[CH3:55]>C(Cl)Cl.C(OCC)(=O)C>[CH2:54]([O:56][C:57]([N:59]1[CH2:60][CH2:61][N:62]([C:1]([CH2:4][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:6])=[O:2])[CH2:63][CH2:64]1)=[O:58])[CH3:55]
Reactant: CC(C)(C)OC(=O)CNc1c(C(=O)CC(=O)O)ccc2ccccc12
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a solution of 2-[carboxymethylcarbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (270 mg, 0.78 mmol) in CH2Cl2 (50 mL) was added triethylamine (0.33 mL, 2.36 mmol) and 1-hydroxybenzotriazole (HOBT) (128 mg, 0.91 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (238 mg, 1.23 mmol). After 5 minutes, 1-ethoxycarbonylpiperazine (0.12 mL, 0.78 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford an oil, which was dissolved in ethyl acetate, and washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated in vacuo and the crude product was purified by flash column to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (147 mg).
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.O1CCCC1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:8])[CH2:27]2)=[O:25])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1ccc(C(=O)C2CCCNC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccc(N)cc2)C1
Reaction time: 1.5 h
Yield: 111.4 %

Procedure:
t-Butyl dicarbonate (0.562 ml, 2.45 mmol) was added to a tetrahydrofuran solution (12 ml) of (4-aminophenyl)(3-piperidinyl)methanone (500 mg, 2.45 mmol) obtained in 1) under ice-cooling, which was stirred for 1.5 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give the titled compound (831 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1([CH2:18][OH:19])[CH2:17][CH:16]=[CH:15][CH2:14]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:19][CH2:18][CH:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCC1CC=CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC1CC=CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Nitrobenzoyl chloride (3.46 g, 18.7 mmol) was added to a dichloromethane solution (34 mL) of cyclopent-3-en-1-ylmethanol (1.67 g, 17.0 mmol) and triethylamine (3.55 mL, 25.4 mmol). The solution was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate solution was added, and the solution was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with 0-100% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CHCl3) δ 2.21 (dd, J=4.9, 14.8 Hz, 2H), 2.57 (dd, J=8.6, 15.1 Hz, 2H), 2.71-2.82 (m, 1H), 4.28 (d, J=7.2 Hz, 2H), 5.69 (s, 2H), 8.19 (d, J=8.6 Hz, 2H), 8.27 (d, J=8.6 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:35])=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CC(C)CS(=O)(=O)Cl
Product: CC(C)CS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(2-Methyl-propane-1-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and 2-methyl-propane-1-sulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:35])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:35])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Yield: 85 %

Procedure:
Intermediate (1b), 2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (2.88 g, 5.78 mmol) was stirred in a mixture of tetrahydrofuran (40 mL) and water (20 mL). Lithium hydroxide (0.469 g, 11.2 mmol) was added and the reaction stirred at reflux for 2 hours. After cooling the reaction mixture was concentrated in vacuo, and the residue was taken up in water and the pH adjusted to 5 with the careful addition of an aqueous 2M hydrochloric acid solution. This aqueous solution was extracted with dichloromethane (×3), and the combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the desired title compound as a yellow solid 2.30 g, 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1([CH3:48])[O:44][C@H:43]([CH2:45][O:46][NH2:47])[CH2:42][O:41]1>C(Cl)(Cl)(Cl)Cl.C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:47][O:46][CH2:45][C@@H:43]3[CH2:42][O:41][C:40]([CH3:48])([CH3:39])[O:44]3)=[O:24])=[C:16]2[N:15]=1
Reactant: CC1(C)OC[C@@H](CON)O1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)OC[C@@H](CONC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)O1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 100 mg, 0.290 mmol) in CCl4 (1.5 mL) was added thionyl chloride (0.10 mL, 1.37 mmol) and the mixture was heated at reflux for 2.5 hours. The mixture was cooled to ambient temperature and was concentrated to give a residual brittle foam. The foam was dissolved in dry THF (2.0 mL) and the solution was sequentially treated with DMAP, DIEA and (S)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (85.5 mg, 0.581 mmol). The reaction was stirred at ambient temperature for 4.5 hours and was concentrated to approx. 0.5 mL. The mixture was diluted with H2O (5 mL) and extracted with 50% EtOAc-hexanes. The combined extracts were washed with 1M HCl, H2O, 1M Na2CO3 and saturated NaCl. The solution was dried over MgSO4 and activated carbon, then filtered through a short SiO2 plug, eluting first with 50% EtOAc-hexanes then 10% MeOH-EtOAc. The MeOH-EtOAc pool was concentrated to give a colorless foam. The foam was dissolved in minimal CH2Cl2 and treated with hexanes to give a white suspension. The suspension was concentrated to afford the title compound as white solid that was dried in vacuum (137 mg, 100%). MS (apci) m/z=474.1 (M+H).
Reaction SMILES: [Cl-].[NH4+].[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:11][C:12]3[C:17]([N+:18]([O-])=O)=[CH:16][C:15]([F:21])=[C:14]([NH:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH3:24])[C:13]=3[F:32])[CH:7]=2)[CH2:5][CH2:4]1.C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:11][C:12]3[C:13]([F:32])=[C:14]([NH:22][C@H:23]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[CH3:24])[C:15]([F:21])=[CH:16][C:17]=3[NH2:18])[CH:7]=2)[CH2:5][CH2:4]1
Reactant: C[C@H](Nc1c(F)cc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1c(F)cc(N)c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of saturated ammonium chloride (4 ml) was added slowly to a suspension of (S)-N1-(5-cyclopropyl-1H-pyrazol-3-yl)-2,4-difluoro-N3-(1-(4-fluorophenyl)ethyl)-6-nitrobenzene-1,3-diamine (Method 102, 0.30 g, 0.719 mmol) and zinc dust (0.235 g, 3.59 mmol) in MeOH/THF (10 ml, 1:1). The mixture was stirred at 25° C. for 2 hours. Saturated ammonium acetate solution (5 ml) was added and the mixture was stirred for another 30 minutes. Zn dust was removed by filtration and the cake was washed with EtOAc (15 ml). The organic layer was separated and dried over sodium sulfate. After removal of solvent, the product was used directly for the next step without further purification.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][NH:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:26]2[CH:25]=[N:24][C:23]([NH:22][CH3:21])=[C:28]([CH3:29])[CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNc1ncc(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)O)n2)cc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (1 g, 2.58 mmol) in toluene (30 mL) and EtOH (10 mL) were added N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (B-4-3) (2 g, 6.3 mmol in theory) and 2 N aq. Na2CO3 (4 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.3 g, 0.26 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. MS showed the reaction was complete and the mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(5-methyl-6-(methylamino)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-4) (0.167 g, 16.98%) as a light yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([O:16][CH3:17])=[O:15]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:11]1[CH:12]=[CH:13][N:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCCN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Br)ccn1C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 40 %

Procedure:
Synthesis was carried out according to the procedure reported: Hasse et al., Aust. J. Chem., 62(7):683-691 (2009). Crystallized (from water) N-bromo succinimide (100 g, 564 mmol) was added to a solution of 1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate (34.0 g, 148 mmol) in carbon tetrachloride (17 L). The resulting suspension was heated at 85° C. for 2 h. The reaction mixture was cooled to 0° C. and the precipitated succinimide removed by filtration. The filtrate was concentrated under reduced pressure. The dark orange oil obtained was subjected to column chromatography (REDISEP®, silica gel, 120 g, 10% EtOAc/hexanes), gave 1-tert-butyl 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate (18.0 g, 39.1%) as an orange color liquid. 1H NMR (400 MHz, CD3OD) 6 ppm: 1.53 (s, 9H), 3.32 (s, 3H), 6.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH2:17])=[CH:5][CH:4]=1.Cl[CH2:24][C:25](Cl)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]([C:10]2[C:11]3[NH:17][C:25](=[O:26])[CH2:24][O:16][C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
N-(4-(trifluoromethyl)benzyl)-2-amino-3-hydroxybenzamide 22a (1 g, 3.2 mmol) was dissolved in 20 ml of DMF and at 0° C. TEA (0.9 ml, 2 equiv.) and chloroacetyl chloride (0.3 ml, 1.2 equiv.) were added. The mixture was stirred at rt for 2 hours. K2CO3 (885 mg, 2 equiv.) was added and the reaction was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 1/petroleum ether 1 as eluant gave 500 mg of a white solid. Yield=44% 1HNMR (DMSO, 200 MHz) δ 4.56 (2H, d, J=5.4 Hz), 4.65 (2H, s), 7.04 (2H, t), 7.17 (1H, d, J=7.8 Hz), 7.55 (2H, d, J=8 Hz), 7.71 (2H, d, J=8.2 Hz), 9.52 (1H, bs), 10.96 (1H, bs); [M+1] 351.1 (C17H13F3N2O3 requires 350.3).