Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:30][C:31]([C@H:33]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34]1)=[O:32])[CH3:29]>C(#N)C.[Cu]I.CNCCNC>[Si:15]([O:14][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([N:34]2[C:35](=[O:38])[CH2:36][CH2:37][C@@H:33]2[C:31]([O:30][CH2:28][CH3:29])=[O:32])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(N2C(=O)CC[C@@H]2C(=O)OCC)cc1
Temperature: 23 °C

Procedure:
To a flask containing acetonitrile was added [(S)-1-(4-bromo-phenyl)-hexyloxy]-tert-butyl-dimethyl-silane and potassium carbonate. The solution mixture was heated to reflux for a period of time. The solution mixture was then cooled to ambient temperature (˜23° C.) before adding a solution of (R)-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester in acetonitrile, CuI and N,N′-dimethylethylenediamine. The reaction mixture was heated to reflux until the ethyl ester was consumed. The reaction mixture was cooled to ambient temperature, filtered through a bed of Celite and rinsed forward with acetonitrile. The filtrate was washed twice with aqueous ammonium acetate and dried over sodium sulfate. The mixture was passed through a bed of silica, washed with MTBE, and concentrated under reduced pressure to give the product as a light yellow oil.
Reaction SMILES: F[C:2]1[C:23]([C:24]2[NH:28][C:27]([CH3:29])=[N:26][N:25]=2)=[CH:22][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:30])[CH:3]=1.CC1NC(C2C=C(C=CC=2F)C([N:43]2[CH2:48][CH2:47][CH:46](C3C=CC(C#N)=CC=3)[CH2:45][CH2:44]2)=O)=C(C)N=1.N1CCCCC1>>[CH3:30][C:4]1[CH:3]=[C:2]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:23]([C:24]2[NH:28][C:27]([CH3:29])=[N:26][N:25]=2)=[CH:22][C:5]=1[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2F)[nH]1
Solvent: C1CCNCC1
Product: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2N2CCCCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 25, except 4-(1-(4-fluoro-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 101.4) was used in place of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1) and piperidine was used in place of azetidine hydrochloride. m/z (ES+) 469 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.NN.Cl.O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12]2)=[CH:27][CH:28]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCC(Oc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
13.8 g (0.04 mol) of 2-{3-[4-(4-fluorophenoxy)-1-piperidyl]propyl}-1H-isoindole-1,3(2H)-dione and 3.9 ml (0.08 mol) of hydrazine in 280 ml of EtOH are reacted for 3 h at the refluxing temperature, and the mixture is then left overnight. 15 ml of concentrated HCl and 20 ml of H2O are then introduced. The mixture is left for 3 hours at the refluxing temperature, then filtered and concentrated. The residue is taken up with water, filtered and rinsed with water. The filtrate is washed twice with ether, then alkalinised with NaOH and extracted 3 times with CH2Cl2. The solution is dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]3[NH:17][N:16]=NN=3)=[CH:10][S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+].C>C(OCC)(=O)C>[CH3:19][C:18]1[O:20][C:13]([C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:12][S:11][CH:10]=2)=[N:17][N:16]=1
Reactant: Cc1ccc(-c2cscc2-c2nnn[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cscc2-c2nnc(C)o2)cc1

Procedure:
A mixture of 5-(4-(4-methylphenyl)-3-thienyl)-tetrazole (3.3 g, 13.2 mmol) and acetic anhydride (50 ml) was heated at reflux temperature for 1 h. The resulting solution was evaporated in vacuo to give an oily residue which was dissolved into ethyl acetate (100 ml). The organic solution was vashed with a sodium bicarbonate solution (100 ml), treated with activated charcoal and dried (MgSO4). Filtration and evaporation in vacuo afforded 3.4 g of 5-methyl-2-(4-(4-methylphenyl)-3-thienyl)-[1,3,4]- oxadiazole as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1B(O)O>C(#N)C.O.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>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:21]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:19])[CH:8]=[N:7]2
Reactant: Clc1cnc2cccc(Br)c2n1
Reactant: Cc1cccc(C)c1B(O)O
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: O
Solvent: CC#N
Product: Cc1cccc(C)c1-c1cnc2cccc(Br)c2n1
Temperature: 80 °C
Yield: 12.2 %

Procedure:
Argon was bubbled into a mixture of 8-bromo-2-chloroquinoxaline (210e; 0.50 g, 2.05 mmol), Na2CO3 (1.09 g, 10.27 mmol), Pd(PPh3)4 (Strem; 0.119 g, 0.103 mmol), 2,6-dimethylbenzeneboronic acid (Aldrich; 0.31 g, 2.05 mmol) in 9 mL ACN and 3 mL water for 1 min. The reaction was sealed and heated to 80° C. overnight. The temperature was increased to 100° C. and the reaction was heated 8 h. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with MeOH/DCM and adsorbed onto 2 g silica gel, dried, and purified by silica gel chromatography (40 g ISCO gold column) using 0-30% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(2,6-dimethylphenyl)quinoxaline (0.08 g, 0.25 mmol, 12% yield) as an oil that solidifies very slowly to a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (1H, s), 8.09-8.19 (2H, m), 7.67 (1H, dd, J=8.2, 7.6 Hz), 7.27-7.33 (1H, m), 7.16-7.23 (2H, m), 2.18 (6H, s). m/z (ESI, +ve) 313.0/315.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:38](F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:38][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(C(F)(F)F)c1)CCC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 539.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3-trifluoromethyl-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C@@H:6]([C:18]2[N:19]([CH3:26])[N:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[O:5][CH2:4]1.[Br:27][C:28]1[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]>>[Br:27][C:28]1[N:33]=[C:32]([C:34]([NH:23][C:22]2[CH:21]=[N:20][N:19]([CH3:26])[C:18]=2[C@H:6]2[O:5][CH2:4][C@H:3]([O:2][CH3:1])[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7]2)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]
Reactant: CO[C@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3ccc(F)c(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following the procedure for Example 65, starting from tert-butyl N-[(3R,4R,7S)-3-methoxy-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (intermediate 93) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with 6-bromo-5-fluoro-pyridine-2-carboxylic acid (see US2010/56576 A1) gave tert-butyl N-[(3R,4R,7S)-7-[4-[(6-bromo-5-fluoro-pyridine-2-carbonyl)amino]-2-methyl-pyrazol-3-yl]-3-methoxy-oxepan-4-yl]carbamate (contaminated with tetramethylurea) as a clear oil (169 mg, 30% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.26-8.17 (m, 2H), 7.63-7.55 (m, 1H), 5.02 (br s, 1H), 4.96 (dd, J=9.0, 3.6 Hz, 1H), 4.32 (dd, J=13.2, 4.4 Hz, 1H), 4.05-3.94 (m, 2H), 3.85-3.80 (m, 1H), 3.78 (s, 3H), 3.47 (s, 3H), 2.10-1.91 (m, 3H), 1.86-1.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]([CH3:18])[CH3:17].C([Li])CCC.[CH:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].O>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH2:22][CH:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])(=[O:21])=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: CCCCC=O
Reactant: COCOc1cc(C(F)(F)F)ccc1N(C(C)C)S(C)(=O)=O
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Reaction time: 1.5 h
Yield: 40.8 %

Procedure:
To a solution of 2-(N-isopropyl-methylsulfonylamino)-5-trifluoromethyl-phenyl methoxymethyl ether (135 mg; prepared in Reference Example 30.) in THF (3.0 ml), hexamethylphosphoramide (420 μl) was added in a stream of argon. At −78° C., n-butyl lithium (742 μl) was added dropwise thereto. The mixture was stirred for 1.5 hours. To the mixture, a solution of valeraldehyde (102 mg) in THF (1.0 ml) was added dropwise. The mixture was stirred for 30 minutes. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated with the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=4:1) to give the title compound (69 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:26]([O:31]C)=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cccnc4OC)c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc2nc(-c3ccnc(-c4ccc[nH]c4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 170 °C
Reaction time: 336 h

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2′-methoxy-2,3′-bipyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (24.2 mg, 0.040 mmol) and lithium iodide (150 mg) in pyridine (2.0 mL) was heated in microwave at 170° C. for 3.5 hours. Reaction mixture was cooled to room temperature and allowed to stand for 14 days, diluted with ethyl acetate. Organic layer was washed with 5% AcOH solution (3×), brine, dried (MgSO4), filtered, concentrated, and purified using Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give desired product. LCMS-ESI+: calc'd for C30H27ClN3O4S: 560.1 (M+H+); Found: 560.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.78 (dd, J=11.1, 6.9 Hz, 2H), 8.28 (d, J=6.0 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=6.1 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.64-7.53 (m, 3H), 6.73 (dd, J=6.8 Hz, 1H), 5.28 (s, 1H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(F)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.28 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10]C(C(F)(F)F)C(C(OCC)=O)=[CH:7][C:6]=2[CH:20]=1.[OH-:21].[Na+]>C1COCC1.C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH:20]=1)[CH:7]=[O:21]
Reactant: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S)c(C=O)c1
Temperature: 25 °C
Reaction time: 88 h
Yield: 51.1 %

Procedure:
The ester from Step 2 (0.55 g 1.8 mmol) was dissolved in THF (1.5 mL) and ethanol (1.5 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8 mmol), and stirred at room temperature for 88 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, filtered, and recrystallized from diethyl ether/petroleum ether to yield the title compound as a yellow solid (0.14 g, 28%): mp 180.8-184.2° C. 1H NMR (acetone-d6/300 MHz) 7.95 (s, 1H), 7.42 (s, 1H), 7.31 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=8.1 Hz), 4.94 (q, 1H, J=8.7 Hz), 2.34 (s, 3H). FABLRMS m/z 281 (M+Li). EIHRMS m/z 274.0250 (M+, Calc'd 274.0275). Anal. Calc'd for C12H9F3O2S: C, 52.55; H, 3.31. Found: C, 52.54; H, 3.35.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([CH:21]=[C:22]([C:24]4[CH:29]=[C:28]([NH:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH:27]=[CH:26][C:25]=4[Cl:38])[N:23]=3)[CH:20]=2)=[CH:11][CH:10]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:38][C:25]1[CH:26]=[CH:27][C:28]([NH:30][C:31]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:32])=[CH:29][C:24]=1[C:22]1[N:23]=[C:18]2[N:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([NH:7][CH3:6])=[CH:14][CH:13]=3)=[CH:20][N:19]2[CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cnc3nc(-c4cc(NC(=O)N5CCCC5)ccc4Cl)cn3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2cnc3nc(-c4cc(NC(=O)N5CCCC5)ccc4Cl)cn3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl(4-(2-(2-chloro-5-(pyrrolidine-1-carboxamido)phenyl)imidazo[1,2-a]pyrimidin-6-yl)phenyl)(methyl)carbamate was treated with 5% TFA in DCM and was stirred overnight at room temperature. At completion, the reaction mixture was concentrated in vacuo and the residue was redissolved in methanol. Purification of the compound was done via mass-triggered reverse phase column chromatography preparative system (15% to 65% (B)). m/z (ESI) for 26: 447.2 (M+H+), 1H NMR (600 MHz, DMSO-D6) δ 9.17 (d, J=2.6, 1H), 8.88 (d, J=2.6, 1H), 8.5, 362 (s, 1H), 8.46 (m, 2H), 7.73 (m, 1H), 7.52 (d, J=8.6, 2H), 7.40 (d, J=8.8, 1H), 6.68 (d, J=8.7, 2H), 5.97 (s, 1H), 3.40 (s, 4H), 2.73 (d, J=5.0, 3H), 1.86 (s, 4H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[O:16].[CH:29](N1CCCCC1)=[O:30].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([CH:29]=[O:30])=[CH:20][C:21]=1[NH:22][C:23](=[O:28])[C:24]([F:25])([F:26])[F:27])=[O:16]
Reactant: O=CN1CCCCC1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)c1sc(C=O)cc1NC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 1.6M n-BuLi solution in hexane (12 mL) was added dropwise to a solution of diisopropylamine (2.9 mL) in THF (30 mL) at −78° C. The reaction mixture was stirred at 0° C. for 10 min and then cooled to −78° C., and a solution of 3-(2,2,2-trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester (1.5 g) in THF (15 mL) was added. The reaction mixture was stirred at −78° C. for 30 min and then 1-formylpiperidine (4 g) was added, and the mixture was again stirred at this temperature for 1.5 h. Subsequently, saturated ammonium chloride solution was added and the reaction mixture was allowed to reach room temperature. The aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The product with the molecular weight of 281.0 (C9H6F3NO4S) was obtained in this way; MS (ESI): 282 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCc2ccc(F)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(F)cc2C1=O
Yield: 71 %

Procedure:
A solution of 19.7 g of 6-fluoro-1-indanone, 27.0 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxypropane was boiled under reflux for 67 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 18.9 g (71%) of (RS)-2-(2-buten-1-yl)-6-fluoro-1-indanone were obtained as a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18](=[O:40])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([N:26](S(CCC)(=O)=O)[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:20]=3[F:39])[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[N:9]=1>CO.O>[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18](=[O:40])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:20]=3[F:39])[CH:15]=2)[NH:10][N:9]=1
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)c(Br)nn3S(=O)(=O)c2ccc(C)cc2)c1F)S(=O)(=O)CCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(Br)c3c2)c1F
Temperature: 60 °C
Yield: 37.2 %

Procedure:
K2CO3 (0.151 g, 1.09 mmol) was added to a solution of N-(3-bromo-1-tosyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.100 g, 0.136 mmol) in MeOH/H2O (4:1, 10 mL), and the reaction mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was taken up in ethyl acetate (100 mL) and washed with water (50 mL). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1), hexanes/ethyl acetate (1:1) to give N-(3-bromo-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.024 g, 37%, 2 steps) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.7 (s, 1H), 8.5 (s, 1H), 7.7 (m, 1H), 7.1 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=472.2, 474.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:7]2.ClS([N:23]=C=O)(=O)=O.Cl>C(#N)C.CO>[NH2:23][C:4]1[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1cc(N)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A 12-L three-neck flask equipped with a mechanical mixer, a condenser, and thermocouple was charged with Compound 4 (0.94 mole, 269.1 g) in acetonitrile (ACN; about 4 L), after which chlorosulfonyl isocyanate (0.99 mole, 86 mL) was added (dropwise) via the dropping funnel. Upon completion of the addition, the resulting reaction mixture was refluxed for about 28 minutes. The pH of the mixture was about 0 at this point. The mixture then was cooled slightly, while adding saturated HCl in methanol (MeOH; 500 mL). Subsequently, the mixture was refluxed for about 1 hour, and then allowed to cool to room temperature overnight, during which time crystals formed. The crystals were collected on a sintered glass frit and rinsed with acetonitrile (400 mL and 500 mL). The filter cake was then transferred to a 12 L reactor with a mechanical stirrer. Deionized (DI) water (900 mL) and saturated Na2CO3 (500 mL) were added to afford mixture having a pH of about 10. Next, the solids in the mixture were collected and slurry rinsed with DI water (3×500 mL). The rinsed product was dried via lyophilization to afford about 268.79 g (63.3% yield) of Compound 5.
Reaction SMILES: C([C:4]1[C:5]([CH3:20])=[N:6][N:7]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([CH3:19])=[N:8]2)(=O)C.Cl>C(O)C>[CH2:12]([N:10]1[C:9]([CH3:19])=[N:8][N:7]2[N:6]=[C:5]([CH3:20])[CH:4]=[C:11]12)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)c1c(C)nn2nc(C)n(Cc3ccccc3)c12
Agent: Cl
Solvent: CCO
Product: Cc1cc2n(Cc3ccccc3)c(C)nn2n1
Reaction time: 6 h
Yield: 95 %

Procedure:
2 g of the 7-acetyl-1-benzyl-2,6-dimethylpyrazolo[1,5-b]-1,2,4-triazole thus-obtained was dissolved in 20 ml of ethanol, to the solution was added 20 ml of concentrated hydrochloric acid and the mixture was refluxed by heating. After about 6 hours, the ethanol was distilled off under reduced pressure, the reaction mixture was rendered alkaline with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate to obtain 1.6 g (95% yield) of almost pure deacetylated compound, i.e., 1-benzyl-2,6-dimethylpyrazolo[1,5-b]-1,2,4-triazole.