Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].ClOC(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][C:32]([NH2:34])=[O:33])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:31]([S:30][C:27]1[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=1)[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)CSc1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)C(Sc1ccc(Cl)cc1)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (-70° C.) solution of 20 g (0.0863 mole) of 2-amino-5-chlorobenzophenone in 500 ml of methylene chloride under nitrogen atmosphere was added a solution of 9.48 g (0.088 mole) of t-butyl hypochlorite in 50 ml of methylene chloride. After an additional 15 min stirring, a solution of 17.35 g (0.0863 mole) of α-(4-chlorophenylthio)acetamide in 500 ml of a 50/50 mixture of tetrahydrofuran and methylene chloride was added. The mixture was stirred at -70° C. for 2 hr, 8.72 g (0.0863 mole) of triethylamine was added, and the stirred solution was allowed to warm to room temperature over a period of 2 hr. The reaction mixture was extracted with several portions of water and the organic layer dried over magensium sulfate. The volume of liquid was reduced to about 500 ml. Methylene chloride, 500 ml, was added to precipitate the product which after filtration and drying weighed 16.62 g (44.7%). The yellow solid melted at 198°-200° C.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].Br[CH2:12][CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:12]([N:3]1[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=2[S:1][C:2]1=[NH:10])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: Nc1nc2c(s1)CCOC2
Solvent: CN(C)C=O
Product: CCCCn1c2c(sc1=N)CCOC2
Temperature: 25 °C
Yield: 101.3 %

Procedure:
A mixture of Example 96A (290 mg, 1.86 mmol) and 1-bromobutane (220 μL, 2.0 mmol) in DMF (400 μL) was heated at 95° C. for 16 hr, cooled to room temperature and quenched with 5 mL of aqueous 1M NaHCO3 solution. The aqueous layer was extracted with dichloromethane (3×5 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 0.4 g of the crude product of the title compound. LC/MS (ESI+) m/z 213 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[H-].[NH2:10][NH2:11]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[CH:6][CH:7]=1
Reactant: NN
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Product: NNc1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
A mixture of 3,6-dichloropyridazine (3 g, 20.14 mmol) and hydrazine monohydride (1 g, 20.14 mmol) was heated in a sealed tube to 80° C. for 5 hours. Solvent was evaporated and the crude was used in the next step without purification (3.56 g, 100%). LCMS (method B): [MH]+=145.1, tR=0.57 min.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=1.[F:27][C:28]([F:37])([F:36])[C:29](N1C=CN=C1)=[O:30]>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[O:26])[CH:23]([CH2:24][CH3:25])[C:29](=[O:30])[C:28]([F:27])([F:36])[F:37])=[CH:20][CH:21]=1
Reactant: CCCC(=O)c1ccc(Br)cc1
Reactant: O=C(n1ccnc1)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(Br)cc1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of hexamethyldisilazane (4.92 g, 30.5 mmol) in THF (10 ml) was added dropwise n-BuLi (1.57 M hexane solution, 19.4 ml, 30.5 mmol) at −78° C. and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled down to −78° C. again and 1-(4-bromophenyl)-1-butanone (5.77 g, 25.4 mmol) in THF (25 ml) was added dropwise over 15 min. The resulting mixture was stirred at −78° C. for 30 minutes, then allowed to warm up to 0° C. and stirred for 40 minutes. The solution was recooled down to −78° C. and N-trifluoroacetylimidazole (5.00 g, 30.5 mmol) was added. The mixture was stirred at −78° C. for 20 minutes, and at room temperature for 2 hours. The reaction was quenched with 2N HCl (30 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed over silica gel with hexane/ethyl acetate (8:1 to 3:1) to give 5.64 g (69%) of the title compound as a oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[N:21]([CH3:32])[C:22]4[C:27]([C:28]=3[C:29]#[N:30])=[CH:26][CH:25]=[C:24]([Cl:31])[CH:23]=4)[CH:19]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[N:21]([CH3:32])[C:22]4[C:27]([C:28]=3[C:29]#[N:30])=[CH:26][CH:25]=[C:24]([Cl:31])[CH:23]=4)[CH:17]=[N:16][CH:15]=2)[CH2:9]1
Reactant: Cn1c(-c2cncc(CN3CC[C@@H](NC(=O)OC(C)(C)C)C3)c2)c(C#N)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(-c2cncc(CN3CC[C@@H](N)C3)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {(R)-1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (140 mg, 0.3 mmol) in dichloromethane (5 mL) is added TFA (2 mL) and the mixture is stirred at room temperature for 2 h. The solvents are then removed in vacuo and the residue is purified by Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to give 2-[5-((R)-3-amino-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.43 (m, 1H), 1.64 (br. s., 2H), 1.97-2.08 (m, 1H), 2.21 (dd, J=9.0, 4.9 Hz, 1H), 2.59-2.68 (m, 1H), 2.71 (dd, J=9.1, 6.6 Hz, 1H), 3.32-3.39 (m, 1H), 3.72 (q, J=13.6 Hz, 2H), 3.79 (s, 3H), 7.36 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.05 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 366.1483 [(M+H)+ Calcd for C20H21ClN5: 366.1485].
Reaction SMILES: Br[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.CC(C)=[O:15].O>>[C:2]12([OH:15])[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1
Reactant: BrC12CCCC(C1)C1CCC2C1
Reactant: CC(C)=O
Solvent: O
Product: OC12CCCC(C1)C1CCC2C1
Reaction time: 1 h
Yield: 95 %

Procedure:
10 Grams (4.4 millimoles) of 1-bromotricyclo [4.3.1.12,5 ] undecane are dissolved in acetone-water (145 ml - 95 ml) and the solution is refluxed under stirring for one hour. After allowing the solution to cool, the solution is extracted with petroleum ether and the extract is dried with anhydrous magnesium sulfate. The solvent is distilled out. The residue is purified by sublimation to obtain 0.69 g (yield 95%) of tricyclo [4.3.1.12,5 ] undecane-1-ol as white crystals.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[N+:49](C1C=CC(N)=CC=1)([O-:51])=[O:50]>C(O)(=O)C>[N+:49]([C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1)([O-:51])=[O:50]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc([N+](=O)[O-])cc1
Yield: 10 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), 4-nitroaniline (225 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 31 mg (0.089 mmol, 10% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C.[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22](Br)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])[CH2:32][CH2:31]1>CN(C=O)C>[NH2:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22]([S:11][C:8]1[S:9][C:10]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=1)[N:23]2[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:47])[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH3:38])[CH2:32][CH2:31]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Br)nc3c(N)ncnc32)CC1
Reactant: Sc1nc2cccc(Cl)c2s1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-Chloro-2-mercaptobenzothiazole (0.020 g, 0.097 mmol) in DMF (2.0 mL) was added (CH3)3COK (0.011 g, 0.97 mmol) at room temperature and stirring continued for 30 min. To the above reaction mixture tert-butyl ((1S)-2-{4-[2-(6-amino-8-bromo-9H-purin-9-yl)ethyl]piperidin-1-yl}-1-methyl-2-oxoethyl)carbamate (0.040 g, 0.081 mmol) in (1 mL) of DMF was added at room temperature. The reaction mixture was heated to 130° C. for 6 h, at the end of this period solvent was evaporated and crude was purified by preparative HPLC [X-Terra prep-RP18 10 um, 19×250 mm (waters), Mobile phase: solvent A: Water HPLC grade containing 0.01% TFA, and solvent B: acetonitrile containing 0.01% TFA, general eluting gradient—solvent B 15% to 80 over 15 to 25 minutes run time]. After lyophilization of HPLC fractions to afford title product. 1H NMR δ (CD3OD), 8.35 (s, 1H), 7.85-7.82 (m, 1H), 7.50-7.40 (m, 2H), 4.40 (t, J=7.2 Hz, 2H), 4.00-3.90 (m, 2H), 1.80-1.70 (m, 4H), 1.21-1.15 (m, 6H), 1.15 (s, 9H), 1.10 (s, 3H); LC-MS [M+H]+ 617.1
Reaction SMILES: [CH2:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]([C:19]([F:22])([F:21])[F:20])[O:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+:29]>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([CH:12]=[C:13]([C:23]([O-:25])=[O:24])[CH:14]([C:19]([F:20])([F:22])[F:21])[O:15]3)=[CH:10][CH:9]=2)=[CH:26][CH:27]=1)[CH3:2].[Na+:29]
Reactant: CCc1ccc(Oc2ccc3c(c2C)OC(C(F)(F)F)C(C(=O)O)=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(Oc2ccc3c(c2C)OC(C(F)(F)F)C(C(=O)[O-])=C3)cc1

Procedure:
A solution of 7-(4-ethylphenoxy)-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid 40.3 mg (0.107 mmole) in 2.0 mL of ethanol was treated with 1.057 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 1.21 (t, 3H, J=7.6 Hz), 2.12 (s, 3H), 2.61 (q, 2H, J=7.6 Hz), 5.87 (q, 1H, J=7.2 Hz), 6.38 (d, 1H, J=8.0 Hz), 6.84 (d, 2H, J=8.0 Hz), 7.00 (d, 1H), J=8.0 Hz), 7.17 (d, 2H, J=8.0 Hz), 7.40 (s, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[CH:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
Ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (1042 g, 4.08 mol, >100%, contaminated with trace DIEA) was dissolved in ethanol (10 L) and to the resulting solution was added a 2M aqueous sodium hydroxide solution (3.87 L, 7.74 mol). The resulting mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure. The resulting residue was diluted with 2 L of water and then washed with methyl t-butyl ether (2×1.2 L). The pH of the aqueous layer was adjusted to pH 4.2-4.5 with a 2N aqueous hydrochloric acid solution. The resulting solids were collected by filtration, washed with water (2 L) and hexanes (2 L) and then dried overnight in a vacuum oven at 45° C. to afford 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (848 g, 96.5% yield over 2 steps) as an off-white solid. MS (ESI) m/z 228.1 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]=2[C:17](=[O:19])[CH3:18])[CH2:4][CH2:3]1.C1CCCCC=1.C1COCC1.O>Cl.[Pd].CCO>[NH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[C:9]=1[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)c1c(N2CCN(C)CC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: O
Product: CC(=O)c1c(N)cccc1N1CCN(C)CC1
Temperature: 70 °C
Yield: 94.5 %

Procedure:
To a solution of 1-[2-(4-methyl-piperazin-1-yl)-6-nitro-phenyl]-ethanone (270 mg, 1.02 mmol) in a mixture (1:1:1.5:2.5) of cyclohexene:THF:H2O:EtOH (12 ml), Pd/C 10% (328 mg) and two drops of HCl 37% were added. The mixture was heated at 70° C. for 3 hours. The Pd was filtered from the reaction and the solvents were removed from the filtrate under reduced pressure. The crude was purified by flash chromatography (DCM/MeOH/7N NH3 in methanol 9:1:1), to give the final compound (225 mg, 95% yield) as orange oil. This was treated with HCl in dioxane, in order to obtain a more manageable solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[N:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=2[CH3:30])[C:9](C2C=CC=CC=2[N+]([O-])=O)=[CH:10][CH:11]=1)[CH3:2].C([O-])=O.[NH4+:35]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[N:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=2[CH3:30])[C:9]([C:21]2[CH:26]=[CH:25][C:24]([NH2:35])=[CH:23][CH:22]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccccc2[N+](=O)[O-])n1-c1ccc(C(N)=O)cc1C
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Reaction time: 24 h

Procedure:
3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(nitro-phenyl)-1H-pyrrole-2-yl]-propanoic acid ethyl ester (83 mg, 0.2 mmol) was dissolved in 2 mL methanol under an inert atmosphere of nitrogen. To this solution was added ammonium formate (117 mg, 1.8 mmol) and 10% Pd/C (10 mg). After 24 hrs, the reaction mixture was filtered using celite, rinsed with MeOH and concentrated in vacuo. The residue was diluted with acetone, filtered and the filtrate concentrated in vacuo to give the crude product, which was purified using preparative TLC (solvent: 5% IPA/CH2Cl2). The band corresponding to 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoic acid ethyl ester (Rf=0.6) was isolated and dried under high vacuum (36 mg, 77%, light orange hydroscopic powder).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCCC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a stirred solution of 2-cyclopropylethanol (5.00 g, 58.05 mmol) in dichloromethane (20 mL) was added pyridine (7.03 mL, 86.92 mmol), followed by p-toluenesulfonyl chloride (10.50 g, 55.07 mmol). The reaction mixture was stirred for 16 h, and then partitioned between dichloromethane (100 mL) and water (50 mL). The organic layer was washed with 10% aqueous hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 2-cyclopropylethyl 4-methylbenzenesulfonate as a colorless oil (11.90 g, 96%): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 4.09 (t, J=6.6 Hz, 2H), 2.45 (s, 3H), 1.57-1.48 (m, 2H), 0.74-0.59 (m, 1H), 0.45-0.36 (m, 2H), 0.08-0.06 (m, 2H).
Reaction SMILES: C[C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1C=CC=C(C)N=1>>[CH3:17][C:4]1[CH:3]=[CH:2][N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=1
Reactant: Cc1cccc(Cl)n1
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Product: Cc1ccnc(N2C[C@@H]3CCNC[C@@H]32)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 40, substituting 2-chloro-4-methylpyridine for 2-chloro-6-methylpyridine in step A. MS (ESI) mass calcd. for C12H17N3, 203.2; m/z found, 204.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:36]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][CH2:30]OS(C)(=O)=O)[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[NH2:43][C:44]1[N:48]=[C:47]([SH:49])[NH:46][N:45]=1>CN(C)C=O>[NH2:43][C:44]1[NH:48][C:47]([S:49][CH2:30][CH2:29][N:27]2[CH:28]=[C:24]([C:23]3[N:18]4[N:17]=[C:16]([NH:15][C:12]5[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[CH:14][CH:13]=5)[N:36]=[C:19]4[CH:20]=[CH:21][CH:22]=3)[CH:25]=[N:26]2)=[N:46][N:45]=1
Reactant: CS(=O)(=O)OCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Reactant: Nc1n[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(SCCn2cc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)cn2)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methanesulfonic acid 2-(4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-ethyl ester (0.40 g, 0.78 mmol) in dimethylformamide (1 ml) was added potassium carbonate (150 mg) followed by 3-amino-5-mercapto-1,2,4-triazole (19 mg, 0.156 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The title compound was purified by preparatory HPLC to yield the desired product. LCMS method: 2, RT: 2.15 min, MI: 532 [M+1]; 1H NMR (300 MHz, DMSO) 9.35 (s, 1H), 8.81 (s, 1H), 8.45 (s, 1H), 8.22 (s, 2H), 7.58 (d, 2H), 7.55 (d, 1H), 7.40 (dd, 2H), 6.85 (d, 2H), 6.13 (s, 1H), 4.51 (t, 2H), 3.98 (t, 2H), 3.48 (t, 2H), 2.75 (t, 2H), 2.49 (s, 4H), 1.65 (s, 4H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[SH:10][CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][S:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: OCCCS
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(SCCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 3-mercapto-1-propanol to afford 4-(3-hydroxypropylthio)benzonitrile. 1.8 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 4-(3-hydroxypropylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(3-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([C:12]([O:14]C(OCC)C)=[O:13])[OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CS(Cl)(=O)=O.[CH2:43]1[CH2:47][O:46][CH2:45][CH2:44]1>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]1[O:13][C:12](=[O:14])[CH:10]([O:11][CH:45]([O:46][CH2:47][CH3:43])[CH3:44])[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(C)OC(=O)C(O)C(NC(=O)OC(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of 497 mg (1.16 mmol) of N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3,3-diphenylisoserine (3) in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25° C. for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF is added and the mixture is stirred at 25° C. for 1.5 hour. The mixture is diluted with 80 mL of hexane and ethyl acetate, and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 243 mg (59%) of 2-tertbutoxy-4,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil. N-debenzoykl-N-tertbutoxycarbonyl-3'-phenyl taxol. To a small reaction vessel is added 90 mg (0.218 mmol) of 2-tertbutoxy-4,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylamino pyridine (DMAP), and 0.029 mL of pyridine. The mixture is stirred at 25° C. for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue is filtered through a plug of silica gel eluted with ethyl acetate. Flash chromatography on silica gel eluted with ethyl acetate/hexane followed by recrystallization from ethyl acetate/hexane gives 44 mg (66%) of N-debenzoyl-N-tertbutoxycarbonyl-2 -(1-ethoxyethyl)3'-phenyl-7-O-triethylsilyl taxol as a ca 3:1 mixture of diastereomers
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([O:18]C)=[O:17])=[CH:8][N:7]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][N:7]=1
Reactant: COC(=O)c1cnc(NCc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(NCc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Yield: 96.3 %

Procedure:
To a mixture of methyl 2-(2,4-dichlorobenzylamino)-4-(trifluoromethyl)pyrimidine-5-carboxylate (443 mg) and ethanol (7 mL) was added a solution of potassium hydroxide (200 mg) in ethanol (4 mL), and the mixture was stirred under heating with reflux for 5 hours. The reaction liquid was concentrated under reduced pressure, water (70 mL) was added to the residue, and the liquid property was made acidic (pH 1) with concentrated hydrochloric acid. The product was extracted with ethyl acetate (200 mL) twice, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 2-(2,4-dichlorobenzylamino)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (411 mg) as a colorless powder.