Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-])=O.[K+].[K+].BrCCCO[C:28]1[CH:33]=[CH:32][C:31]([C:34]2(C=O)[CH:39]=[CH:38][CH:37]=[CH:36][CH2:35]2)=[CH:30][C:29]=1[O:42][CH3:43]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH:4]([O:8][C:29]4([O:42][CH3:43])[CH:28]=[CH:33][CH:32]=[C:31]([C:34]5[CH:35]=[CH:36][C:37]([CH:17]=[O:20])=[CH:38][CH:39]=5)[CH2:30]4)[CH2:3][CH3:2])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Agent: [K+]
Solvent: CC#N
Product: CCC(OC1(OC)C=CC=C(c2ccc(C=O)cc2)C1)N1CCC(c2noc3cc(F)ccc23)CC1
Yield: 172.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (2.3 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off and the solvent was evaporated to an oil. Purification was carried out by flash chromatography over a silica gel column (SIO2, 50 g; eluted with dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2% methanol: 98% dichloromethane, 600 ml). The fractions containing the pure product were combined and concentrated to give 4.24 g (87%) of an off-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of 1 -[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3-yl)-I -piperidinyl]-propoxy]-3-methoxyphenyl]phenylmethanone as off-white crystals, m.p.=128°-130° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4]1.[Br:16]Br.C1CCN2C(=NCCC2)CC1>CC#N>[C:5]1(=[O:13])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:3][CH2:4]1.[Br:16][C:4]1[C:3]([C:2]([F:14])([F:15])[F:1])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:13]
Reactant: O=C1CC(C(F)(F)F)Cc2ccccc21
Reactant: BrBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCCc2ccccc21
Product: Oc1c(Br)c(C(F)(F)F)cc2ccccc12

Procedure:
Treatment of 3-(trifluoromethyl)-3,4-dihydro-1(2H)-naphthalenone (178) (0.40 g, 1.87 mmol) with bromine followed by DBU in CH3CN gave 0.23 g (43% from tetralone) of the title compound (179) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.45 (s, 1H), 7.58-7.68 (m, 2H), 7.83 (s, 1H), 7.84-7.90 (m, 1H), 8.28 (d, J=7.5 Hz, 1H). LCMS (ESI): m/z 289 (M−H)−.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1)C1C=CC=CC=1.[ClH:16].[H][H]>CO.[Pd]>[ClH:16].[CH3:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([OH:15])[CH2:11]1
Reactant: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H]1CNC[C@@H](O)C1

Procedure:
To a solution of (S)-1-benzyl-5-methyl-piperidin-3-one (0.9 g, 4 mmol) was dissolved in methanol, 25% aq, hydrochloric acid solution added until the pH was acidic, followed by palladium (10% on activated charcoal, 0.2 g). The mixture was stirred under 1 atmosphere of hydrogen (balloon) for 6 h. The reaction was then filtered through Hyflo and concentrated to afford the title product as a white powder (0.66 g, quant). MS (ISP)=116.1 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:26][C:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=4[N:29]=3)=[CH:23][CH:24]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(O)c1ccc(OCCF)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCF)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 4-(2-fluoroethoxy)benzoic acid (0.20 g, 1.11 mmol) and thionyl chloride (0.53 g, 4.44 mmol) in chloroform (5 ml) was heated under reflux for 5 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.28 g, 1.11 mmol) in dry pyridine (10 ml) to give the title compound (0.34 g, 72%) as a pale yellow solid after work-up.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A stirred solution of 1-methylpiperazine (14.6 mL) and triethylamine (19.2 mL) in dry dichloromethane (132 mL) at 10° C. was treated with 4-nitrobenzoyl chloride (23.2 g) portion wise whilst maintaining the temperature below 15° C. After stirring at 10° C. for a further 1 hour the reaction mixture was allowed to warn to room temperature and treated with water (100 mL). The organic phase was then separated and the aqueous phase further extracted with dichloromethane (50 mL). The combined organic extracts were washed with a 0.5 M aqueous solution of sodium carbonate (100 mL), then with brine (100 mL), and then evaporated to low bulk and treated with petroleum ether (80–100° C.) (100 mL). After removal of further solvent, and trituration, the insoluble material collected was washed with petroleum ether (40–60° C.) to give the title compound (30.4 g) as pale orange crystalline solid, m.p. 100–101° C. 1H NMR [(CDCl3]: δ 8.29 (d, 2H), 7.59 (d, 2H), 3.94–3.71 (bs, 2H), 3.52–3.29 (bs, 2H) and 2.58–2.30 (2×brs and s overlapping, 7H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.C(N(CC)CC)C>CO.[Pd]>[CH3:26][N:25]([CH3:27])[C:23]([C:20]1[O:21][C:22]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=[CH:17][C:18]=2[CH:19]=1)=[O:24]
Reactant: CN(C)C(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reaction time: 3 h
Yield: 88.1 %

Procedure:
The reaction mixture of 7-(4-benzylpiperazin-1-yl)-N,N-dimethylbenzofuran-2-carboxamide (0.70 g, 1.93 mmol) and acetic acid (0.44 mL, 7.70 mmol) in methanol (30 mL) was debenzylated in a H-cube for 3 h at 50° C. using Catcart 30 Pd/C cartridge. Triethylamine (1.1 mL, 7.9 mmol) was added and the solvent was removed in vacuo. The crude material was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-10%) to give 0.47 g (1.70 mmol) of product in 88% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[F:8][C:4]1[N:3]=[C:2]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)n1
Reactant: OB(O)c1cccs1
Product: Fc1cccc(-c2cccs2)n1

Procedure:
2-Bromo-6-fluoropyridine and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(6-fluoro-2-pyridyl)thiophene as yellow oil. APCI-Mass m/Z 180 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[CH3:16][S-:17].[Na+]>CS(C)=O>[CH3:16][S:17][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)Cc1cc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
A solution of methyl 5-fluoro-2-nitrophenylacetate (3 g, 14 mmol), (Synthesis 1993, 51), in DMSO (10 ml) was added to a suspension of sodium thiomethoxide (1.08 g, 15.5 mmol) in anhydrous DMSO (10 ml). The mixture was stirred for 10 minutes at ambient temperature and further sodium thiomethoxide (100 mg, 1.5 mmol) was added. The mixture was stirred for 15 minutes at ambient temperature and was then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (15/85) to give methyl 5-methylthio-2-nitrophenylacetate (2.68 g, 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.CN(C)CCN(C)C.C([Li])CCC.[I:26]CI>O.C(OCC)C>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[C:7]([I:26])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: ICI
Reactant: CC1(C)CCOc2ccccc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCOc2c(I)cccc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2.00 g (12.3 mmol) of 4,4-dimethylchroman and 30 ml of ethyl ether are introduced into a three-necked flask under argon. 2.4 ml (15.9 mmol) of tetramethylethylenediamine (TMEDA) are added dropwise, the mixture is cooled to −78° C. and 5.9 ml (14.8 mmol) of n-butyllithium (2.5M in hexane) are added dropwise. The temperature is allowed to return to −20° C. over two hours and then to room temperature and the mixture is stirred for 12 hours. 1.3 ml (16.0 mmol) of diiodomethane and 15 ml of ethyl ether are introduced into another three-necked flask under argon. Cooling is carried out to 0° C. and the preceding solution, cooled beforehand to −78° C., is introduced, then the reaction mixture is allowed to return to room temperature and stirred for 12 hours. The reaction mixture is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, 1.30 g (37%) of the expected compound are collected in the form of a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:24](O)([CH3:27])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Temperature: 40 °C
Yield: 86.1 %

Procedure:
To a solution of 5-bromo-2-chlorobenzoic acid (11.75 g) in N,N-dimethylformamide (50 ml) was added 1,1′-carbonyldiimidazole (8.10 g), and the mixture was stirred under heating at 40° C. for one hour. Thereto were added t-butanol (7.40 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.60 g), and the mixture was further stirred under heating at 40° C. overnight. The mixture was diluted with diethyl ether, and washed successively with water (3 times), 2% aqueous hydrochloric acid solution (twice), a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give t-butyl 5-bromo-2-chlorobenzoate (12.53 g) as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[N:3]=1.[ClH:11]>C(O)C.CO.O.[Pd]>[ClH:11].[ClH:11].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1nc(N)ccc1CN
Reaction time: 25 h
Yield: 94 %

Procedure:
A mixture of 2-amino-5-cyano-6-methylpyridine (4.0 g, 30.0 mmol) and 10% Pd/C (3.08 g) in ethanol (80 mL), methanol (30 mL), concentrated HCl (6 mL) and water (10 mL) was shaken on a Parr apparatus at 60 psi for 25 h. The reaction was filtered through celite, rinsing with 1:1 ethanol/methanol and was evaporated in vacuo to a solid, which was triturated with 5:1 ethyl acetate/ethanol to give the title compound (5.95 g, 94%):
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)[CH3:2].F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.O.OC1C2N=NNC=2C=CC=1.[C:46]([NH:49][NH2:50])(=[O:48])[CH3:47].C(N(C(C)C)C(C)C)C>ClCCl.O>[C:46]([NH:49][NH:50][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]([O:13][CH3:14])=[N:5][C:6]=1[CH3:12])(=[O:48])[CH3:47]
Reactant: CCc1cc(C(=O)O)c(C)nc1OC
Reactant: CC(=O)NN
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(=O)NNC(C)=O)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 143.5 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask, 5-ethyl-6-methoxy-2-methyl-nicotinic acid (500 mg, 2.56 mmol) of Step 2, Example 14 is dissolved in dichloromethane (30 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (990 mg, 3.33 mmol) is added, followed by hydroxybenzotriazole hydrate (510 mg, 3.33 mmol). The resulting mixture is stirred at rt for 45 min to give a suspension, which is treated with acetic hydrazide (285 mg, 3.85 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol). The resulting solution is stirred at rt for 32 hr, LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with six portions of dichloromethane, the combined extract is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1, increasing to 1:2). Fractions containing the product are combined and evaporated to obtain 5-ethyl-6-methoxy-2-methyl-nicotinic acid N′-acetylhydrazide (give 923 mg) as a white solid. MS: m/e=252 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.72 (1H, d), 8.50 (1H, d), 7.49 (1H, s), 3.96 (3H, s), 2.59 (3H, s), 2.54 (2H, q), 2.12 (3H, s), 1.17 (3H, t).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:50]#[N:51])=[CH:45][C:46]([F:49])=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccc(F)cc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A mixture of hydroxylammonium chloride (2.4 g), sodium hydrogencarbonate (3.6 g) and dimethyl sulfoxide (40 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-4-fluorobiphenyl-2-carbonitrile (2.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (40 mL). N,N′-Carbonyldiimidazole (1.1 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.99 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (1.5 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([OH:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23](OC(=O)C)[CH3:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([O:14][CH2:23][CH3:24])=[O:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCCCCCC(C(=O)O)S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Product: CCCCCCC(C(=O)OCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
By the procedure described in Example 1(b), 2.6 g (60% of theory) of 2-[(4-methylphenyl)sulfonyl]octanoic acid, MP 111°-123° C. (acetic acid ethyl ester), is obtained from 4.75 g (14.5 mmol) of ethyl 2-[(4-methylphenyl)sulfonyl]octanoate (Example 13) and 32 ml of 1N potash lye.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C@@H:14]2[CH2:18][O:17][CH2:16][C@H:15]2[OH:19])=[CH:11][CH:10]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[CH3:22][S:23]([O:19][C@H:15]1[C@H:14]([O:13][C:12]2[CH:20]=[CH:21][C:9]([Br:8])=[CH:10][CH:11]=2)[CH2:18][O:17][CH2:16]1)(=[O:25])=[O:24]
Reactant: O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Triethylamine (181.9 mL, 1.31 mol) was added to a solution of trans-4-(4-bromophenoxy)tetrahydrofuran-3-ol from the previous step (354 g, assumed 300.6 g, 1.16 mol) in methylene chloride (2 L), and the reaction was cooled to 0° C. in an ice bath. Methanesulfonyl chloride (101.3 mL, 1.31 mol) was then added drop-wise, while keeping the reaction temperature below 5° C., and the reaction was stirred at room temperature for 18 hours. Water (1.5 L) was added, and the aqueous layer was extracted with methylene chloride. The organics were combined and dried over sodium sulfate, filtered and concentrated in vacuo to afford product as a brown oil. Yield: 399.6 g, 1.18 mol, quantitative. Material from a smaller-scale experiment carried out in similar fashion was triturated with ethanol for characterization. 1H NMR (400 MHz, CDCl3) δ 3.10 (s, 3H), 4.00 (br dd, J=10.4, 1.9 Hz, 1H), 4.07 (m, 1H), 4.16 (dd, J=11.1, 3.9 Hz, 1H), 4.23 (dd, J=10.5, 4.6 Hz, 1H), 4.98 (br d, J=4.6 Hz, 1H), 5.20 (m, 1H), 6.85 (d, J=9.1 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:28][CH:24]3[CH2:25][NH:26][CH2:27][CH:23]3[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:22][CH:23]3[CH2:27][N:26]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:25][CH:24]3[CH2:28]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CNCC5C4)n3)cc2nn1C
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CN(C(=O)CC#N)CC5C4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 86.4 %

Procedure:
To a solution of 5-chloro-N2-(2,3-dimethyl-2H-indazol-6-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (484.7 mg, 1.22 mmol) and 2-cyanoacetic acid (155.0 mg, 1.82 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (673.2 mg, 1.77 mmol) and Et3N (0.60 g, 5.90 mmol). The reaction mixture was stirred at rt for 5.5 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to give the title compound as a beige solid (0.49 g, 87%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])C1C=C(C=CC=1)CCOC1C=CC([N+]([O-])=O)=CC=1.[F:23][C:24]([F:56])([F:55])[C:25]1[CH:26]=[C:27]([CH:52]=[CH:53][CH:54]=1)[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([C@:40]([NH:44]C(=O)OC(C)(C)C)([CH3:43])[CH2:41][OH:42])=[O:39])=[CH:33][CH:32]=1.C(N[C@](C)(C(O)=O)CO)(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:96](=[O:99])([O-:98])N>CCN(C(C)C)C(C)C>[F:1][C:2]([F:22])([F:21])[C:96]([OH:98])=[O:99].[F:23][C:24]([F:55])([F:56])[C:25]1[CH:26]=[C:27]([CH:52]=[CH:53][CH:54]=1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:39])[C@:40]([NH2:44])([CH3:43])[CH2:41][OH:42])=[CH:35][CH:36]=1
Reactant: NC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)C(=O)Nc1ccc(OCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCc2cccc(C(F)(F)F)c2)cc1
Agent: CC(C)(C)OC(=O)N[C@@](C)(CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@](N)(CO)C(=O)Nc1ccc(OCCc2cccc(C(F)(F)F)c2)cc1
Product: O=C(O)C(F)(F)F
Yield: 47.9 %

Procedure:
1-(3-(trifluoromethyl)phenethyloxy)-4-nitrobenzene (470 mg) was converted to 290 mg tert-butyl (S)-2-(4-(3-(trifluoromethyl)phenethyloxy)phenylcarbamoyl)-1-hydroxypropan-2-ylcarbamate following the general procedure provided in Example 5(A) employing N-(Boc)-α-methylserine (210 mg), HATU (360 mg), and DIPEA (900 μl). MS (ESI, M+H+)=483.4. The carbamate (145 mg) was deprotected following the procedure in Example 5(A) yielding 143 mg of the title compound. MS (ESI, M+H+)=383.1. 1H NMR (400 MHz, DMSO-d6) δ 9.8 (bs, 1H), 7.67–7.40 (m, 6H), 6.88 (m, 2H), 5.67 (bs, 1H), 4.18 (t, 3H), 3.91 (m, 1H), 3.58 (m, 1H), 3.11 (t, 3H), 1.41 (s, 3H).