Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:16])=[CH:5][CH:4]=1>[Pd].C(O)C>[NH2:13][C:12]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:16])[NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc2cc[nH]c(=O)c2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1N)C(=O)NCC2
Temperature: 40 °C
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A suspension of 7-methoxy-8-nitroisoquinolin-1(2H)-one (296b, 30 g, 0.136 mol) and 10% palladium on carbon (15 g, 0.014 mol) in ethanol (1 L) was stirred at 40° C. under hydrogen (20 psi) for 72 hours. The mixture was filtered through celite, the flask and filter pad washed with ethanol (1 L), and the combined filtrates concentrated under vacuum to give 8-amino-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296c, 24 g, 92% yield) as a brown oil. MS: 193 [M+1].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:22](O)=[O:23])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:22]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:23])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (319 μl) was condensed with Boc-3-(2-thienyl)-L-alanine (900 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-[Boc-3-(2-thienyl)-L-alanyl]morpholine (1.13 g) as a colorless oily product (yield quantitative). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (315 mg) to yield the title compound (compound 73; 563 mg) as a white powder (yield 75%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[NH:9][C:10]([C:12]3[C:16]([NH2:17])=[CH:15][NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[C:29]([NH:17][C:16]1[C:12]([C:10]2[NH:9][C:8]3[CH:18]=[CH:19][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=3[N:11]=2)=[N:13][NH:14][CH:15]=1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]cc3N)nc2c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1c[nH]nc1-c1nc2cc(C(=O)O)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester [200 mg, Example 233(k)] in tetrahydrofuran (5 ml) was added diisopropylethylamine (545 μl) and isobutyryl chloride (327 μl) dropwise and the reaction stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was taken up in 1M potassium hydroxide in tetrahydrofuran/methanol (1:3, v/v) (5 ml) and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was taken up in 1M sodium hydroxide in water/methanol (5 ml) and stirred for 1 hour. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water and the layers separated. The aqueous layer was acidified to pH 3-4 with 5% citric acid solution, extracted with ethyl acetate and the organic layer washed with brine. The organic layer was then dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (140 mg) as a white solid. LC-MS (METHOD C): RT=2.87 minutes, 313.33 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9][NH2:10].[F:20][C:21]([F:28])([F:27])[C:22]([CH3:26])([CH3:25])[CH:23]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([O:11][Si:12]([CH2:15][CH3:16])([CH2:17][CH3:18])[CH2:13][CH3:14])[CH2:9][NH:10][CH2:23][C:22]([CH3:26])([CH3:25])[C:21]([F:28])([F:27])[F:20]
Reactant: CC(C)(C=O)C(F)(F)F
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cncc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC[Si](CC)(CC)OC(CNCC(C)(C)C(F)(F)F)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a yellow clear mixture of 2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (3.57 g, 11.11 mmol) in DCM (37.0 mL) was added 3,3,3-trifluoro-2,2-dimethylpropanal (11.11 mmol) in DCM followed by AcOH (0.770 ml, 13.33 mmol) and NaBH(OAc)3 (3.53 g, 16.67 mmol). The yellow heterogeneous mixture was stirred at room temperature. After 8 h, the mixture was quenched with saturated NaHCO3 (100 mL). The reaction mixture was extracted with DCM (2×100 mL). The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 20% EtOAc in heptane to provide N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2-dim ethylpropan-1-amine (A294) (3.4393 g, 7.72 mmol, 69.5% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (2H, s), 5.48 (1H, dd, J=7.7, 4.4 Hz), 3.27 (1H, dd, J=12.3, 8.4 Hz), 2.58-2.83 (3H, m), 1.25-1.44 (1H, m), 1.10 (6H, s), 0.85-0.94 (9H, m), 0.47-0.64 (6H, m); LCMS (ESI) m/z 445.1 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[N:15]=[C:16]=[S:17]>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[N:15]1[C:16]([SH:17])=[N:3][N:2]=[N:1]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(OC)c(N=C=S)c1
Agent: [Na+]
Solvent: O
Product: COc1ccc(OC)c(-n2nnnc2S)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium azide was dissolved in water in an amount corresponding to 1.1 equivalent to 2,5-dimethoxyphenylisothiocyanate, and cooled. Thereto, 2,5-dimethoxyphenylisothiocyanate was slowly added. After the conclusion of the addition, the mixture was stirred at a room temperature for 30 minutes and then, it was refluxed for 4 hours as heat was applied thereto. At the conclusion of the reaction, the reaction mixture was cooled and neutralized to produce crystals of 1-(2,5-dimethoxyphenyl)-5-mercaptotetrazole.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([S:16]([NH2:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: NS(=O)(=O)c1cccs1
Product: NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
4-biphenylsulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-biphenylsulfonyl chloride, which afforded the title compound 642.2 mg (90.6%) as a white solid, m.p.: 223-225° C.
Reaction SMILES: C(NCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:33]([C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1)=O.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46].[BH3-]C#N.[Na+]>>[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH:46][CH2:33][C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CC(C)(C)CN
Agent: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)CNCc1ccc(B(O)O)s1
Yield: 100.4 %

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (2,2-dimethylpropyl)amine (0.037 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 21 mg of the title compound (21%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nn2c(-c3ccc(Cl)c(N(C)S(C)(=O)=O)c3)ccnc2c1C#N
Yield: 60.7 %

Procedure:
A mixture of 0.048 g (0.39 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 89 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 60.5%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCOCC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and morpholine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=373.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][CH:20]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: Fc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1cccc(N[C@H]2CCN(Cc3ccccc3)C2)c1
Yield: 88.8 %

Procedure:
A toluene solution containing 2.2 g of (S)-1-benzylpyrrolidin-3-ylamine (12.5 mmol), 2.2 g of 3-bromofluorobenzene (12.5 mmol), 0.31 g of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 0.51 mmol), 0.14 g of bis(dibenzylideneacetone)palladium (Pd(dba)2, 0.22 mmol), and 1.3 g of sodium tert-butoxide (13.2 mmol) was heated under reflux under a nitrogen atmosphere for 3 hours. The reaction solution was filtered to remove insoluble matter, and ethyl acetate and water were added to the filtrate to separate the solution into layers. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→1:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 3.0 g of oily colorless ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15]([OH:17])=O)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]=2[C:15]2[O:17][C:22]([C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[O:19][CH3:18])=[N:24][N:25]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1c(-c2ccccc2)noc1C1CC1
Reactant: COc1ccccc1C(=O)NN
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Reaction time: 18 h
Yield: 32.7 %

Procedure:
To a suspension of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid (236 mg, 1.03 mmol) in dichloromethane (2 mL) were added 2-methoxybenzhydrazide (205 mg, 1.24 mmol), 2-chloro-1,3-dimethylimidazolium chloride (383 mg, 2.26 mmol) and triethylamine (0.52 ml, 5.15 mmol) at ambient temperature. The resulting suspension was stirred for 18 h at this temperature before diluting with dichloromethane (20 ml) and washing with water (20 mL) and brine (20 mL). The aqueous layers were extracted with dichlormethane and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (121 mg, 33%) as a white solid. MS: m/e=360.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:30]2[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=2)[CH:3]=[CH:4][C:5]=1[F:26])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Reactant: OB(O)c1cncc(F)c1
Product: Cc1cc(C2(c3cc(-c4cncc(F)c4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 41 %

Procedure:
The title compound was synthesized as described for Example 1 in 41% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol) and 5-fluoropyridin-3-ylboronic acid (35.4 mg, 0.25 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[C:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:12])[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH2:13]([C:9]1([CH3:12])[C:8]2[CH:20]=[CH:21][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[O:11][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(Cc2ccccc2)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.5 %

Procedure:
A mixture of 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (300 mg, 1.06 mmol) obtained in Example 4(B), sodium hydroxide (260 mg, 6.5 mmol), ethanol (10 ml) and water (1 ml) in tetrahydrofuran (10 ml), is stirred for 12 h at room temperature. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product is obtained as a white solid (300 mg, 100%). Mp: 165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.C(O)=O.CS(O)(=O)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CSc1ccccc1F)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: O=CO
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(CSc1ccccc1F)c1ccc(F)cc1
Yield: 95.6 %

Procedure:
The crude ester from Step B (5.3 g, 16 mmole) was combined with 20 ml of 88% formic acid and 2.1 ml (33 mmole) of methane sulfonic acid. The emulsion was refluxed for five hours during which time it gradually became homogeneous. After cooling, water and methylene chloride were added and the aqueous phase was separated and extracted twice with methylene chloride. The organic phases were combined, dried (MgSO4) and concentrated. The crude residue was taken up in 4% ethyl acetate/hexane and filtered through a plug of silica gel to remove nonpolar impurities. The product acid was then rinsed from the silica gel with ethyl acetate and the solvent concentrated. The acid was a colorless solid (4.5 g, 95% yield). 1H NMR (CDCl3) δ: 10.05 (1H, br s), 7.20 (5H, m), 7.03 (3H, m), 3.81 (1H, dd, J=6, 8 Hz), 3.57 (1H, m), 3.23 (1H, dd, J= 6, 12 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)[CH:13]=1.[C:20](#[N:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:21]([CH3:23])([CH3:22])[C:20]#[N:24])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(F)cc(Br)c1
Reaction time: 20 h
Yield: 100 %

Procedure:
At 2-5° C. a solution of lithium bis(trimethylsilyl)amide in THF (326 ml of 1 M, 326 mmol, 1.05 equiv.) was added dropwise into a solution of 1-bromo-3,5-difluorobenzene (60 g, 311 mmol, 1.0 equiv.) and isobutyronitrile (25.8 g, 373 mmol, 1.2 equiv.) in 360 mL of THF. After stirring for 20 h, 13% starting reagent remained so an additional 0.1 eq of lithium bis(trimethylsilyl)amide was added. After an additional 6 hr, 10% starting reagent remained so another 0.1 eq. of lithium bis(trimethylsilyl)amide and 0.1 eq. of isobutyronitrile were added. The reaction mixture was stirred overnight. The reaction mixture was quenched with a 1 N HCl solution, then concentrated down to remove some of the THF. The reaction mixture was extracted with methyl-tert-butyl ether (2 times) and concentrated under reduced pressure to get the crude product (75.3 g) which was used as is.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:13]([NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:36])[CH3:35])=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:35])[CH3:36])=[C:14]([O:16][CH2:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1OCC1CCNCC1
Yield: 72.6 %

Procedure:
A solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(2-(dimethylamino)acetamido) pyridin-4-yloxy)methyl)piperidine-1-carboxylate (24 mg, 0.047 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (10 mL) was stirred for 45 minutes. The solution was concentrated and the residue was loaded onto a MP-TsOH SPE cartridge. Elution with 2M ammonia in methanol gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethoxy)pyridin-3-yl)-2-(dimethylamino)acetamide as a yellow solid (14 mg, 72%).
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:20][C:21]1[CH:22]=[C:23]([C:27]([CH3:42])([CH3:41])[C:28]([CH:30]([C:36](OCC)=[O:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Br:20][C:21]1[CH:22]=[C:23]2[C:24]([C:36]([OH:37])=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:28](=[O:29])[C:27]2([CH3:41])[CH3:42])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reaction time: 2 h
Yield: 41.1 %

Procedure:
H2SO4 (60 mL, 710 mmol) was cooled to 0° C. and treated with P2O5 (20 g, 141 mmol). The mixture was brought to room temperature and added to diethyl 2-(2-(3-bromophenyl)-2-methylpropanoyl)malonate (17.44 g, 45 mmol). The reaction mixture was then stirred for 2 hours. Ice (H2O) was added, and the aqueous mixture was extracted with EtOAc (3×). The combined organic layers were washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude compound as an orange oil. The crude oil was purified by silica flash chromatography (0-100% DCM/hexane) to give the desired compound as a white solid (6.27 g). MS (m/e)=339.1 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[S:7][C:6]([C:8](OC)=[O:9])=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[F:1][CH:2]([F:12])[C:3]1[S:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(C(F)F)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a mixed solution of methyl 5-(difluoromethyl)thiophene-2-carboxylate (2.23 g) in tetrahydrofuran (60 ml) and methanol (15 ml) was added sodium borohydride (2.2 g) at room temperature, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.94 g).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[CH2:10]([SH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](=[O:5])[S:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: CCCCCCCCS
Product: CCCCCCCCSC(=O)CC(F)=C(F)F
Temperature: 70 °C
Yield: 91.3 %

Procedure:
A mixture of 3,4,4-trifluoro-3-butenoyl chloride (1.7 g, 0.0107 mole) and 1-octanethiol (0.72 g, 0.0049 mole) is heated at 70° C. for 12 h. The crude product is purified by passing through a short column of silica gel to give 1.2 g of the desired product as a pale yellow oil, a 91% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH2:30][OH:31]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][OH:31])[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: OCCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCO)C3)c2n1

Procedure:
Prepared similarly to Example 1 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine (for example, as prepared for Intermediate 26) and 2-bromoethanol (commercially available, for example, from Aldrich).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12]>[I-].[Na+].C1(C)C(C)=CC=CC=1>[CH2:10]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CNCC(C)C
Reactant: CCOC(=O)CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCN(CC(C)C)CC(C)C
Yield: 39.4 %

Procedure:
To 180 ml of xylene were added 176 grams of ethyl gamma-chlorobutyrate, 302.2 grams of diisobutylamine and 6.0 grams of sodium iodide and the mixture was heated to reflux on an oil bath of 120° to 140° C. for 62 hours. After cooling, salts separated out therefrom were removed by filtration, the filtrate was washed with ether, concentrated, and the residue was distilled in vacuo to give 112 grams of the colorless oily product, b.p. 102-6° C./2 mmHg.