Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:21]=1.N(CC)CC>C1COCC1.[Cu](I)I>[CH3:1][N:2]1[CH2:6][CH2:5][C@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:21]=2)[C:3]1=[O:18]
Reactant: C#CC[C@@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
Copper iodide (22.64 mg, 0.1200 mmol), followed by PdCl2(Ph3P)2 (41.73 mg, 0.060 mmol) was added portionwise to a solution of tert-butyl N-[(3R)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 10) (300 mg, 1.19 mmol), 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 12) (584.44 mg, 1.61 mmol) and Et2NH (0.62 mL, 5.95 mmol) in THF (10 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The solvent was evaporated and the residue was purified by Biotage SP4, using a 25 g SNAP cartridge, eluting with 0 to 100% EtOAc/i-hexane affording tert-butyl N-[(3R)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (D13) (482 mg, 0.987 mmol, 83.0% yield) as a pale yellow foam.
Reaction SMILES: [CH2:1]([C:8]1([C:21]([OH:23])=O)[CH2:20][CH:11]2[CH2:12][N:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CC(C)=O.O>[CH2:1]([C:8]1([C:21]([N:37]=[N+:38]=[N-:39])=[O:23])[CH2:9][CH:10]2[CH2:14][N:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:12][CH:11]2[CH2:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)O)CC2C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)N=[N+]=[N-])CC2C1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
5-Benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 14c (0.86 g, 2.72 mmol) was dissolved in 30 mL of acetone upon cooling by an ice-water bath. When the mixture was cooled to −5° C., a solution of triethylamine (0.303 g, 2.99 mmol) and ethyl chloroformate (0.325 g, 2.99 mmol) in 15 mL of acetone were added dropwise successively. The reaction mixture was stirred for 15 minutes followed by dropwise addition of a solution of sodium azide (0.353 g, 5.44 mmol) in 15 mL of water. The reaction mixture was stirred for another 30 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carbonyl azide 14d (0.9 g, yield 97%) as a light yellow oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].Cl[C:7]1[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:13][C:9]=2[N:10]=[CH:11][N:12]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.ClCCl.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[C:8]3[C:7]([O:4][CH2:3][CH2:2][CH2:1][OH:5])=[N:12][CH:11]=[N:10][C:9]=3[O:13][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1
Reactant: OCCCO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCO)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Put 1.13 g (14.85 mmol) 1,3-propanediol in 30 ml THF. Add 833 mg (7.42 mmol) potassium tert.-butylate and stir for 15 min at RT. Then cool to 0° C. and add a solution of 1.0 g (2.97 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 15 ml THF dropwise over a time of 30 min. Then leave to return to RT and stir for a further 2 h. Dilute with dichloromethane and water, acidify with 10% citric acid solution and separate the phases. Extract the aqueous phase once with dichloromethane. Combine the organic phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate, concentrate by evaporation and purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 7:3→1:1). 772 mg (69.0% of theor.) of the target compound is obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][C:22]1([NH2:26])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:22]([NH2:26])([CH3:21])[CH2:23]4)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(N)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(N)CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 86.9 %

Procedure:
A mixture of 0.5 g (1.8 mmol) of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.34 g (2.1 mmol) of 3-methyl-3-aminoazetidine hydrochloride and 0.5 ml of triethylamine in 10 ml of pyridine is heated to reflux for 3 hours. The mixture is allowed to cool and is filtered and the product is washed with water. 0.52 g of 1-cyclopropyl-6-fluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, melting point 285°-7° C., is thereby obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:36])=[C:20]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]5([C:33]#[N:34])[CH2:32][CH2:31]5)[CH:25]=4)[CH:21]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].C(N(CC)CC)C.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C>[C:33]([C:30]1([C:26]2[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=2)[C:23]([NH:22][C:20]2[CH:21]=[C:16]([O:15][C:13]3[CH:12]=[CH:11][C:9]4[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:48]5[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]5)[S:7][C:8]=4[CH:14]=3)[CH:17]=[CH:18][C:19]=2[CH3:36])=[O:35])[CH2:32][CH2:31]1)#[N:34]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CN4CCN(C)CC4)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
N-[5-({2-[(Chloroacetyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-methylphenyl]-3-(1-cyanocyclopropyl)benzamide synthesized above was dissolved in tetrahydrofuran (5.0 mL), triethylamine (188 μL, 1.36 mmol) and 1-methylpiperazine (152 μL, 1.36 mmol) were added, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate/hexane to give the title compound (141 mg, 36%) as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[CH2:14][N:13]1[C:30](=S)[CH2:31][C:32](=[N:34][N:35](C(OC(C)(C)C)=O)[CH3:36])[CH3:33])=[O:11].C(OC(C)=O)(C)C>ClCCl>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:28])([F:29])[F:27])(=[O:19])=[O:18])[CH2:14][N:13]1[C:30]1[N:35]([CH3:36])[N:34]=[C:32]([CH3:33])[CH:31]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=NN(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.7 %

Procedure:
Trifluoroacetic acid (61 ul, 0.8 mmol) was added to a solution of (2S,4R)-1-[3-(tert-butoxycarbonyl-methyl-hydrazono)-thiobutyryl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (90 mg, 160 umol) in dichloromethane (0.3 ml) under an argon atmosphere. The mixture was stirred at ambient temperature for 72 h. Ice water/10% aqueous sodium carbonate solution 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted four more times with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc) to obtain the title compound (20 mg, 46 umol; 29%) as yellow solid. MS (ESI): m/z=432.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[CH:34]=[CH:33][C:18]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:34][CH:33]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1)=[O:6]
Reactant: FC(F)(F)c1cccc(CCNCc2ccc(C3CC3)cc2)c1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Nc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 53 mg of 2-amino-5-chloro-benzoic acid (0.33 mmol) and 105 mg (0.33 mmol) of (4-cyclopropyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 4.5 ml of DMF were added 171 mg of HBTU (0.45 mmol) and 0.1 ml (0.9 mmol) of 4-methyl-morpholine. After stirring the reaction mixture over night at RT it was diluted with 50 ml water and extracted with ethyl acetate. The combined organic phases were washed with 10% aqueous KHCO3 solution, 0.1M HCl solution and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The remaining oil was purified by column chromatography (silica gel; heptane/EtOAc 6:1) to give 127 mg (88%) of 2-amino-5-chloro-N-(4-cyclopropyl-benzyl)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as a yellow oil. MS (ISP) 473 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH:15]1([C:18]2[CH:22]=[C:21]([NH2:23])[NH:20][N:19]=2)[CH2:17][CH2:16]1>CCCCO>[Br:8][C:7]1[C:2]([NH:23][C:21]2[CH:22]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[NH:19][N:20]=2)=[N:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][CH:6]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Brc1cnc(-c2ccccc2)nc1Br
Solvent: CCCCO
Product: Brc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 64 %

Procedure:
To a solution of 4,5-dibromo-2-phenylpyrimidine (0.82 g, 3.29 mmol, 1.0 eq) in n-BuOH (20 mL), 3-cyclopropyl-1H-pyrazol-5-amine (0.811 g, 6.58 mmol, 2 equiv.) was added and the reaction mixture was heated to 90° C. for 24 hours, filtered to produce 5-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (Compound 8) (0.75 g, 64.1%). LC-MS (m/z): 357.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 0.74-0.77 (m, 2H), 0.98-1.02 (m, 2H), 1.96-2.01 (m, 1H), 6.40 (s, 2H), 7.50-7.54 (m, 3H), 8.27-8.30 (m, 2H), 8.63 (s, 1H), 8.88 (s, 2H), 12.32 (s, 1H).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[P:8]([O-:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[Na+]>C(#N)C>[N:3]1([CH2:2][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: ClCn1cncn1
Reactant: CCOP([O-])OCC
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=O)(Cn1cncn1)OCC
Yield: 56.2 %

Procedure:
A mixture of 18.2 g (0.155 mole) of 1-chloromethyl-1H-1,2,4-triazole, 27.2 g (0.17 mole) of sodium diethyl phosphite and 200 ml of acetonitrile is heated for 2 hours to 60° C. and then refluxed for 16 hours. The precipitate is removed and the solution is concentrated. Fractional distillation of the residue yields 19.1 g (56.5%) of diethyl (1H-1,2,4-triazol-1-yl)methylphosphonate in the form of a colourless oil with a boiling point of 120°-129° C./0.053 mb.
Reaction SMILES: Cl.[C:2]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][Cl:23])=[N:20][C:19]([C:24]([OH:26])=[O:25])=[N:18]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27]O>>[CH3:27][O:25][C:24]([C:19]1[N:20]=[C:21]([CH2:22][Cl:23])[N:17]([C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:2](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:18]=1)=[O:26]
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 18 h

Procedure:
224 ml of a 6 N solution of hydrogen chloride in methanol is added to a solution of 112.2 g (0.299 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid in 1120 ml of methanol, and the whole is refluxed for 21 hours. There is then distilled off 800 ml of methanol at normal pressure, and the concentrated solution is allowed to stand for 18 hours at room temperature. The product that has crystallised out is filtered off under suction and washed with cold methanol and hexane. After drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 132°-134°.
Reaction SMILES: Br[CH:2]1[CH2:6][O:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[CH2:3]1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+].C(#N)C>C(OCC)(=O)C.CCCCCC>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:4]1[O:5][CH2:6][CH:2]([S:17][C:15](=[O:18])[CH3:16])[CH2:3]1
Reactant: Fc1ccc(C2CC(Br)CO2)c(F)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: CC(=O)SC1COC(c2ccc(F)cc2F)C1
Yield: 76.7 %

Procedure:
The title compound is prepared by the procedure of Example 5 using 1.9 g of product from Example 165, 0.866 g of potassium thioacetate and 30 ml of acetonitrile to give, after chromatography (silica gel: 5% ethyl acetate/hexane), 1.43 g of the desired product, as a mixture of isomers.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3cccc(F)c3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3cccc(F)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.07 g of 4,5-bis(4-methoxyphenyl)-2-(3-fluorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 3.04 g of 4,5-bis(4-methoxyphenyl)-2-(3-fluorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:44]=[N:43][C:34]2[NH:35][C:36](=[O:42])[C:37]([CH3:41])([CH3:40])[NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:40][C:37]1([CH3:41])[C:36](=[O:42])[NH:35][C:34]2[N:43]=[CH:44][C:31](/[CH:11]=[CH:10]/[C:9]([N:8]([CH2:7][C:6]3[CH:14]=[CH:15][CH:16]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=3[O:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[O:12])=[CH:32][C:33]=2[CH2:39][NH:38]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(C(C)C)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1C(C)C
Yield: 31 %

Procedure:
A solution of N-(3-isopropyl-2-propoxybenzyl)-N-methylacrylamide (0.397 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.40 mL, 2.33 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were then added and the mixture deoxygenated with Ar for 20 min. The mixture was heated to reflux for 18 h, then allowed to cool. The solution was diluted with EtOAc (30 mL) and H2O (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 95:5) gave the title compound (0.16 g, 31%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.77 (m, 1H), 8.40-8.35 (m, 1H), 8.01-7.91 (m, 1H), 7.55-7.48 (m, 1H), 7.31-7.20 (m, 2H), 7.10-7.03 (m, 1H), 6.88-6.85 (m, 1H), 4.81-4.66 (m, 2H), 3.90-3.83 (m, 2H), 3.77-3.69 (m, 2H), 3.32-3.25 (m, 1H), 3.12-2.90 (m, 4H), 1.81-1.77 (m, 2H), 1.31-1.28 (m, 6H), 1.19-1.17 (m, 6H), 1.06-1.01 (3H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C(OC(C)C)(C)C.N1CCCCC1>[CH:4]([O:15][CH:14]([CH3:16])[CH3:13])([CH3:9])[CH3:5].[CH3:19][O:18][C:12](=[O:17])[C:13]([C:14](=[O:15])[CH3:16])=[CH:10][C:9]1[C:4]2=[N:3][O:2][N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cccc2nonc12
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Product: COC(=O)C(=Cc1cccc2nonc12)C(C)=O
Temperature: 70 °C
Yield: 177.7 %

Procedure:
Suspended 2,1,3-benzoxadiazole-4-carboxaldehyde (50 g, 0.33 mote) in diisopropyl ether (1300 ml) and added methyl acetoacetate (38 g, 0.32 mole), piperidine (2 g) glacial acetic acid (6 g) in to the suspension one after another. Refluxed the reaction mixture at 70° C. with continuous water separation. Removed sample from the reaction mixture and analysed the samples by qualitative HPLC. Washed the reaction mixture with hydrochloric acid (˜3.5 wt %, 250 ml, sodium bicarbonate solution (˜10 wt %, 250 ml and water (250 ml, 100 ml. Dried the organic layer over sodium sulphate (25 g) and then distilled diisopropyl ether under vacuum to get crude 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester (yield 70 g, HPLC purity 93.4%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18](I)[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[F:24][C:25]([F:64])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:44]=3B3OC(C)(C)C(C)(C)O3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.C>[Pd](Cl)Cl.C(P(CCCC)[C-]1C=CC=C1)CCC.[C-]1(P(CCCC)CCCC)C=CC=C1.[Fe+2]>[C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([C:44]3[CH:45]=[CH:46][C:47]([C:49]([F:52])([F:51])[F:50])=[CH:48][C:43]=3[CH2:42][N:38]3[C@@H:37]([CH3:62])[C@@H:36]([C:28]4[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=[C:26]([C:25]([F:24])([F:63])[F:64])[CH:27]=4)[O:40][C:39]3=[O:41])[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCCP(CCCC)[c-]1cccc1
Product: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of 2-[4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]-2-oxoethyl acetate (Step A; 33 mg; 0.076 mmol) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Intermediate 9; 68 mg, 0.114 mmol) was treated with 1,1′-bis(di-1-butylphosphino)ferrocene palladium dichloride (˜5 mg) as described earlier. The product was purified by chiral HPLC (ChiralPak IA column, 15% IPA/heptane) to afford 2-{4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidin-1-yl}-2-oxoethyl acetate as a colorless glass. LCMS=779.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.86 (s, 1H), 7.69 (s, 2H), 7.68-7.60 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 6.96-6.91 (m, 1H), 6.72 (dd, J=11.9, 2.1 Hz, 1H), 5.59-5.54 (m, 1H), 4.90 (d, J=15.6 Hz, 1H), 4.80-4.65 (m, 3H), 4.13-4.04 (m, 1H), 3.88-3.72 (m, 2H), 3.78 (s, 3H), 3.21-3.04 (m, 2H), 2.72-2.67 (m, 1H), 2.17 (s, 3H), 1.96-1.83 (m, 2H), 1.70-1.59 (m, 2H), 0.42-0.39 (m, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.Br.[Br:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][NH2:54].C(N(CC)CC)C>CN(C=O)C>[Br:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][NH:54][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:26]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(CN)CBr
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(C)(C)CBr)c2n1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B; 150 mg, 0.420 mmol), EDCI (88.5 mg, 0.462 mmol), and HOBT-H2O (70.7 mg, 0.462 mmol) in DMF (10 mL) was added 3-bromo-2,2-dimethylpropan-1-amine hydrobromide (124 mg, 0.504 mmol) followed by triethylamine (55.2 mg, 0.546 mmol). The reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 50% EtOAc/Hexanes to provide (R)-N-(3-bromo-2,2-dimethylpropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (180 mg), to which was added HCl (5 mL, 4M in dioxane). The reaction was sealed and heated to 90° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 20% Hexanes/EtOAc to provide the desired product (130 mg, 63% yield).