Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C@@H:10]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]#[CH:29])[CH3:25].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][C@@H:10]([CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:11][NH2:12])[C:2]([C:29]#[C:28][CH:27]([O:30][CH2:31][CH3:32])[O:26][CH2:24][CH3:25])=[CH:7][N:6]=1
Reactant: CC(C)C[C@@H](CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: C#CC(OCC)OCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1cnc(Cl)nc1N[C@H](CN)CC(C)C)OCC
Temperature: 25 °C

Procedure:
To a solution of tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate 5.0 g (12.3 mmole) in toluene (36 mL) and triethyl amine (7.2 mL) was added under nitrogen, 3,3-diethoxyprop-1-yne 2.8 mL (19.7 mmole), Pd2(dba)3 1.1 g (1.23 mmole), and triphenylarsine 3.8 g (12.3 mmole). The contents were heated to 70 degrees for 24 hrs. After cooling to room temperature, the reaction mixture was filtered through CELITE™ and then concentrated under vacuum. The crude product was columned over silica gel using hexane/ethyl acetate (0-30%) to afford (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. LCMS (ESI) 455 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]3[C:17]([O:18]CC)=[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[N:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[CH2:26](Br)[CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][N:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:9]=[CH:10][C:11]=2[C:17](=[O:18])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15]1
Reactant: OCCBr
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1OCC
Product: CCOC(=O)c1cn(CCO)c2nc(N3CCN(C)CC3)ncc2c1=O

Procedure:
Following the procedure described in Example 37 using ethyl 2-(4-methyl-1-piperazinyl)-5-ethoxypyrido-[2,3-d]pyrimidine-6-carboxylate with ethylenebromohydrine, there is obtained the product, m.p. 197 - 199°C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+].O>S(=O)(=O)(O)O>[CH2:10]([C:3]1[C:4]([F:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1c(F)ccc(F)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCc1c(F)c(F)cc([N+](=O)[O-])c1F
Yield: 81.6 %

Procedure:
2,3,6-Trifluoro-1-ethylbenzene (1.09 g) is dissolved in conc. sulfuric acid (5.5 ml), and thereto is added with stirring a mixture of potassium nitrate (0.83 g) in conc. sulfuric acid (4 ml) at room temperature, and the mixture is stirred at the same temperature for one hour. The reaction mixture is poured into cold water (100 ml) and is extracted with diethyl ether. The ether layer is washed with aqueous sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.14 g), as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.[NH2:14][C@@H:15]([CH2:23][OH:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:15]([NH:14][C:11](=[O:13])[CH:10]=[CH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:23][OH:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: N[C@@H](CO)Cc1ccccc1
Product: COc1ccc(C=CC(=O)NC(CO)Cc2ccccc2)cc1

Procedure:
Prepared in a similar manner as described in example 4 from 3-(4-methoxy-phenyl)-acrylic acid and D-phenylalaninol. MS (M+H, 312.3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and methanesulfonyl chloride (40 mg, 0.35 mL) at ice-bath. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 365.2.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:4]([CH3:13])[C:5]([C:8]([O:10]CC)=O)=[N:6][N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([NH:22][C:8]([C:5]1[N:4]([CH3:13])[C:3]([N:2]([CH3:1])[CH3:14])=[N:7][N:6]=1)=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1nnc(N(C)C)n1C
Solvent: C1CCOC1
Product: CN(C)c1nnc(C(=O)NCc2ccccc2)n1C
Yield: 34.5 %

Procedure:
6 g (0.03 mole) of ethyl 5-dimethylamino-4-methyl-4H-1,2,4-triazol-3-yl-carboxylate and 4.28 g (0.04 mole) of benzylamine are heated in 80 ml of tetrahydrofuran at 200° C. at 20 bar. For working up, the mixture is evaporated in vacuo, and the residue is purified on silica gel by means of chromatography (eluent: toluene/ethanol 1:1). 2.68 g (35% of theory) of N-benzyl-5-dimethylamino-4-methyl-4H-1,2,4-triazol-3-yl-carboxamide of melting point 96° C.-98° C. are obtained.
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C@:14]1([CH2:23][O:24][SiH:25]([CH3:27])[CH3:26])[OH:22])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].O>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:20])([CH3:21])[CH3:19])[C@:14]1([CH2:23][O:24][SiH:25]([CH3:27])[CH3:26])[O:22][CH3:1])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: C[SiH](C)OC[C@]1(O)[C@H](C(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@]1(CO[SiH](C)C)[C@H](C(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
In DMF (10 ml), methyl iodide (0.53 ml, 8.51 mmol) was added to N-benzyloxycarbonyl-(2R)-tert-butyldimethylsilyloxymethyl-(3S)-hydroxypyrrolidine (2.60 g, 7.11 mmol) and sodium hydride (0.34 g, 14.2 mmol) under stirring at 0° C. The reaction mixture was stirred further at the same temperature for 13 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, N-benzyloxycarbonyl-(2R)-tert-butyldimethylsilyloxymethyl-(3S)-methoxypyrrolidine (2.73 g, 100%) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([OH:13])[CH2:4][CH2:3]1.[H-].[Na+].F[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[CH:22]=1>CN(C=O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6]([C@H:5]([O:13][C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=4)[CH:22]=3)[CH2:4][CH2:3][C@@H:2]2[NH2:1])=[CH:7][CH:8]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccc(F)cc21
Reactant: CC(C)c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4cc(F)ccc43)cn12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
Intermediate 19a (837 mg, 4.62 mmol) was dissolved in dry DMF (15 mL) under Ar, then NaH (60% in mineral oil, 556 mg, 13.9 mmol) was added, and the mixture stirred for 15 min. Intermediate 1f (893 mg, 4.99 mmol) was added, and the reaction heated at 60° C. for 2 h. The reaction was cooled, quenched by addition of water and extracted with DCM (4×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC, eluting with 0-20% [2M NH3 in MeOH] in DCM, to give the title compound (429 mg, 27%). LCMS (Method 3): Rt 1.96, m/z 363 [MNa+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])C2.[CH3:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25]([OH:27])=O)[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.C([O:33]CC)C>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6](=[O:11])[O:33][C:4]=4[CH:3]=3)=[O:27])[CH2:22][CH2:23]2)=[CH:29][CH:30]=1
Reactant: CCOCC
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: Cc1ccc(CC2CCN(C(=O)C(=O)O)CC2)cc1
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
The title compound is prepared from 5-amino-1,3-dihydro-indol-2-one and [4-(4-methyl-benzyl)-piperidin-1-yl)-oxo-acetic acid according to the method described in Example 1c. Melting Point: 216-220° C. (diethylether)
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:47])([F:46])[C@H:25]([CH3:45])[O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56]>>[Cl:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][C@@H:25]([CH3:45])[C:24]([F:23])([F:46])[F:47])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]3)[C:30]2=[N:35]1
Reactant: Clc1ccccc1CBr
Reactant: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3[nH]nnc23)C1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3nn(Cc4ccccc4Cl)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N—{(S)-1-[5-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-acetamide and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 484.4 (MH+).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[C:10]([OH:14])(=[O:13])[CH:11]=[O:12]>>[CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][C:7]([CH:11]([OH:12])[C:10]([OH:14])=[O:13])=[CH:8][C:3]=2[O:2]1
Reactant: O=CC(=O)O
Reactant: c1ccc2c(c1)OCO2
Product: O=C(O)C(O)c1ccc2c(c1)OCO2

Procedure:
Addition reaction step in which 1,2-methylenedioxy-benzene and glyoxylic acid are reacted in the presence of a strong acid to form 3,4-methylenedioxymandelic acid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]([N:27]=C=O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[C:19]([NH:27][C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([NH:45][C:41]1[CH:42]=[CH:43][C:44]2[N:32]([CH2:30][CH3:31])[C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:18])=[O:7])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CC#N)CN3C(=O)NC(=O)c3ccccc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=492.4.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH-:19].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1
Reactant: COc1ccccc1C[NH-]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
5.7 g of 4-(trifluoromethyl)benzoic acid and 4.0 g of 2-methoxybenzylamide were dissolved in 100 ml N,N-dimethylformamide, and 4.8 ml diethyl cyanophosphonate and 4.2 ml triethylamine were added under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours, then poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 8.7 g of N1-(2-methoxybenzyl)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[NH4+].[Cl-]>C(Cl)Cl>[CH2:8]([C:4]1[C:3]([CH3:16])=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(O)cccc1C(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(O)cccc1Cc1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
A solution of (3-hydroxy-2-methylphenyl)(phenyl)methanone prepared as in Step 2 (1.60 g, 7.54 mmole) in anhydrous CH2Cl2 (70 mL) was cooled to 0° C. Triethylsilane (32.5 mL, 203 mmole) and TFA (52.3 mL, 679 mmole) were added in portions at 0° C. over a period of 3 days with the mixture brought back to reflux after each addition. After 3 days, the mixture was cooled, poured into sat. NH4Cl (200 mL) and extracted with CH2Cl2 (3×200 mL). The combined extracts were washed with H2O (200 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by silica chromatography (95:5 hexanes:EtOAc) to give 1.19 g (80% yield) of the product as a pale yellow oil: EIHRMS m/z 198.1072 (M+, C14H14O, Calc'd 198.1045).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23](Br)=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]([F:38])([F:37])[F:26])=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [K+]
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(-c3ccccc3C(F)(F)F)c2n1
Yield: 91.9 %

Procedure:
Following procedures of example 14, (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.250 g, 0.62 mmol), 2-trifluoromethylphenyl boronic acid (0.1538 g, 0.81 mmol), potassium carbonate (0.1292 g, 0.93 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0360 g, 0.03 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4 g SiO2, 0-100% ethyl acetate in hexanes) to give (2S)-benzyl-2-(8-(2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.264 g, 0.57 mmol, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:45][O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50]>ClCCl.O>[CH3:45][O:46][C:47](=[O:51])[CH2:48][CH2:49][NH:50][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:25][CH:24]=2)[CH2:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Reactant: COC(=O)CCN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Racemic 4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid (7.46 g, 17.89 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.23 g, 18.43 mmol) and 4-methylmorpholine (2.07 mL, 18.78 mmol) are combined in anhydrous dichloromethane (100 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. Beta alanine methyl ester hydrochloride (2.76 g, 19.68 mmol) and 4-methylmorpholine (4.14 mL, 37.56 mmol) is added to the reaction mixture and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with dichloromethane. The reaction is diluted with water and rinsed with 1N hydrochloric acid. Upon acidification, the two layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated. Flash column chromatography gave the title compound (7.07 g, 14.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[CH2:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.Br[CH2:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH:12]=[CH:13][C:17]2[N:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[CH2:15]1)(=[O:11])[CH3:10]
Reactant: Clc1ccc(CBr)c(Cl)n1
Reactant: C=Cc1ccc(Cl)cc1NC(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2ccc(Cl)nc2C=Cc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 6C and 13B by a route analogous to that used for the preparation of 1D. HPLC Rt=2.769 min; LCMS Found: (M+H)+=319.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][CH2:4][C@@H:5]([NH:17][C:18](=O)[O:19]C(C)(C)C)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7].F[C:27](F)(F)C(O)=O>ClCCl>[C:18]([NH:17][C@H:5]([CH2:4][O:3][CH:2]([F:25])[F:1])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7])(=[O:19])[CH3:27]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Solvent: ClCCl
Product: CC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Yield: 65.7 %

Procedure:
tert-Butyl {(1R)-1-[(difluoromethoxy)methyl]-2-[(4-fluorobenzyl)amino]-2-oxoethyl}carbamate (400 mg, 1.1 mmol) was stirred with trifluoroacetic acid (1.5 mL) and dichloromethane (2.5 mL) in an ice bath for an hour. The reaction mixture was concentrated, mixed with acetic anhydride-pyridine (1:1.6 mL) at room temperature for 30 minutes and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, 0.5N HCl and brine again. The organic layer was dried, concentrated, and triturated with diethyl ether to give (2R)-2-(acetylamino)-3-(difluoromethoxy)-N-(4-fluorobenzyl)propanamide (220 mg, 65.7%) as a white solid. Mp: 162.7° C. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.24 (dd, 2H), 7.03 (t, 2H), 6.78 (w, 1H), 6.35 (d, 1H), 6.24 (wt, 1H), 4.71 (m, 1H), 4.44 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:33]1[S:42][CH2:41][C@H:40]2[C@:35]([C:43]3[S:44][CH:45]=[C:46](Br)[CH:47]=3)([CH2:36][CH2:37][O:38][CH2:39]2)[N:34]=1)C(=O)C1C=CC=CC=1)=O)(C)(C)C.C(OCC)(=O)C>CN(C=O)C.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>[F:1][C:2]1[C:7]([C:46]2[CH:47]=[C:43]([C@@:35]34[N:34]=[C:33]([NH2:24])[S:42][CH2:41][C@@H:40]3[CH2:39][O:38][CH2:37][CH2:36]4)[S:44][CH:45]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@@]2(c3cc(Br)cs3)CCOC[C@H]2CS1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)cs3)CCOC[C@H]2CS1
Temperature: 90 °C
Reaction time: 7 h
Yield: 36.1 %

Procedure:
2-Fluoropyridine-3-boronic acid (15.7 mg), tetrakis(triphenylphosphine)palladium (4.3 mg) and a 1 N sodium carbonate solution (112 μL) were added to a solution of (±)-N-tert-butoxycarbonyl-N-[(4aS*,8aS*)-8a-(4-bromo-thiophen-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azanaphthalen-2-yl]benzamide (20.0 mg) in DMF (1 mL). After replacement with nitrogen, the mixture was stirred at 90° C. for seven hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (4.7 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.[NH2:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[F:36][C:33]([F:34])([F:35])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:16]2[N:17]=[N:18][C:13]([NH:12][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][C:2]([F:1])([F:11])[F:10])=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:26]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)COCCC(F)(F)F
Product: O=C(COCCC(F)(F)F)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use (3,3,3-trifluoropropoxy)acetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (50% yield). 1H NMR (300 MHz, CDCl3) δ 9.03, 8.32, 7.75, 7.63, 7.56, 7.37, 7.03, 4.13, 4.03-3.98, 3.94-3.89, 3.84, 3.71-3.63, 3.60-3.58, 3.35-3.32, 2.56-2.48. MS (ES+) m/z 506.5 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH2:3][O:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.CCOCC>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: OCc1ccc2c(c1)COC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)COC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1,3-Dihydro-isobenzofuran-5-yl)-methanol (440 mg, 2.9 mmol) was dissolved in 20 ml of DCM. 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin reagent) (1.3 g, 3.2 mmol) was added and the reaction was stirred at r.t. for 4 h. The reaction mixture was diluted with ether and extracted 2× with NaOH 1N, 2× with H2O and dried over MgSO4. The crude product was sufficiently pure and used without any further purification.