Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[C:23]([F:28])[CH:22]=2)=[N:16]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[C:23]([F:28])[CH:22]=2)=[N:16]1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)c(F)c3)[nH]c2=O)c1
Yield: 12.8 %

Procedure:
The title compound was prepared according to the procedure, described in Example-111 by using N-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (step 1 of Example-149, 0.080 g, 0.155 mmol), ethynylcyclopropane (0.019 g, 0.233 mmol), TBAF (0.121 g, 0.466 mmol), bis(triphenylphosphine)palladium(II) chloride (0.004 g, 0.006 mmol) and DMSO (3.0 mL) to afford 0.009 g of the desired product. 1H NMR (300 MHz, DMSO 4): δ 0.79-0.92 (m, 2H), 1.011 (m, 2H), 1.30 (s, 6H), 1.63 (m, 1H), 2.39 (m, 1H), 4.28 (d, J=5.7 Hz, 2H), 7.35 (m, 1H), 7.43 (s, 1H), 7.57-7.67 (m, 4H), 8.37 (m, 1H); MS (m/z): 453.24 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[S:21][C:22]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])[CH2:4][CH2:3]1.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:20]1[S:21][C:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]([C:16](=[O:17])[NH:15][C:10]2[CH:11]=[N:12][N:13]([CH3:14])[C:9]=2[N:5]2[CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]2)[N:19]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
(R)-tert-butyl 4-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate (112 mg, 0.204 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (95 mg, 0.409 mmol) were dissolved in methylene chloride/DMF (1.5 mL/1.5 mL). N,N-diisopropylethylamine (132 mg, 1.02 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove DMF, redissolved in ethyl acetate and washed with brine. The aqueous layer was extracted with ethyl acetate 3×. Combined organic layers were concentrated and purified by flash chromatography eluted with 0 to 100% ethyl acetate in heptane to give (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(4-(2,2,2-trifluoroethylamino)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (96 mg, 75%), which was deprotected by 4N HCl in dioxane and purified on reversed phase HPLC to give 197. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.59-7.43 (m, 4H), 7.25 (t, J=8.7 Hz, 2H), 3.64 (s, 3H), 3.24-3.01 (m, 6H), 2.81 (s, 1H), 2.14 (d, J=6.1 Hz, 1H), 1.96-1.74 (m, 3H), 1.65-1.48 (m, 3H). MS (ESI) m/z: 530.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Cl:28][CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:32]([OH:34])([CH3:33])[CH2:31][CH2:30][CH2:29][Cl:28])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CC(=O)CCCCl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(C)(O)CCCCl)nc3N21
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
A solution of 0.30 g (0.81 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 20 ml diethyl ether was cooled to −100 deg C. and treated dropwise with 65 μl (0.97 mmol) tert-butyllithium (1.5 M solution in n-pentane). After 15 min, 0.12 g (0.11 ml, 0.98 mmol) 5-chloro-2-pentanone was added, the temperature was allowed to rise to −75 deg C. and after an additional 15 min, the reaction was quenched with 10%. aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to afford the compound as a colorless oil (50.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:29](=[O:36])[C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1ccncc1

Procedure:
2-Chloro-4-(2-{4-[3-isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with isonicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 502. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.9 (d, 2H)) 8.5 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 2H) 7.9 (m, 1H) 7.5 (d, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.5 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: CO.[Na].CO[C:6](=O)[CH2:7][N:8](C=O)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.[CH:21]([O:23][CH3:24])=[O:22].Cl.[S-:26][C:27]#[N:28].[K+]>O1CCCC1.O>[CH3:24][O:23][C:21]([C:7]1[N:8]([CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)[C:27]([SH:26])=[N:28][CH:6]=1)=[O:22]
Reactant: COC(=O)CN(C=O)Cc1cc(F)cc(F)c1
Reactant: COC=O
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Methanol (1.54 ml, 0.0381 mole) was added to a suspension of sodium (0.876 g, 0.0381 mole) in dry tetrahydrofuran and the mixture stirred for 30 minutes. A solution of N-formyl-N-(3,5-difluorobenzyl)-glycine methyl ester (8.50 g, 0.0349 mole) in methyl formate (6.57 ml, 0.107 mole) was added dropwise with cooling at 10° to 15° C. and the resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was diluted with 100 ml water-methanol (1:1). The solution was treated with activated carbon, filtered, and cooled in ice. Hydrochloric acid (12N, 6.4 ml) and a solution of potassium thiocyanate (4.25 g, 0.0437 mole) in a minimum amount of water were added and the resulting solution was heated at 65°-70° C. for 24 hours. The solution was treated with activated carbon, filtered and the solvent was removed under vacuum until a precipitate formed. The mixture was cooled in ice and the product filtered and washed with a mixture of methanol-water. The product was trituarted with ethanol, filtered and dried to give a solid melting at 177°-178° C. (6.75 g, 68%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C@@H:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:17]1([NH:20][C:21]([C:23]2[CH:24]=[C:25]([F:33])[C:26]([CH3:32])=[C:27](B(O)O)[CH:28]=2)=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CC(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>[CH:17]1([NH:20][C:21]([C:23]2[CH:24]=[C:25]([F:33])[C:26]([CH3:32])=[C:27]([C:2]3[N:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([CH3:10])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:15][CH:16]=3)[CH:28]=2)=[O:22])[CH2:19][CH2:18]1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)nc1)C(C)(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)(C)C)cn1
Temperature: 90 °C

Procedure:
6-Chloro-N-[(R)-3,3-dimethyl-2-butyl]nicotinamide (Intermediate 11, 100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH2:9][CH3:10])[O:4][C:3]1=[O:11].[H][H]>[Pd].C(O)C>[CH3:1][C@H:2]1[CH2:6][C@@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[O:4][C:3]1=[O:11]
Reactant: [H][H]
Reactant: C=C1CC(CCCC)OC1=O
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@@H]1C[C@H](C)C(=O)O1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
3-Methylene-5-butyldihydro-2(3H)-furanone (5.8 g; 0.33 mole) was charged to a reactor with 0.25 g 5% palladium on carbon and 6 mls ethanol. The mixture was stirred at room temperature and hydrogen gas slowly introduced subsurfacely for eight hours. The catalyst was removed by filtering and the solvent evaporated under reduced pressure to yield 5.3 g of cis- 3-methyl-5-butyldihydro-2(3H) furanone (84% assay by GLC;86.5% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[CH:32]1([N:38]=[C:39]=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CO.CC#N>CN(C=O)C>[CH:32]1([NH:38][C:39]([NH:29][C:28]2[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:13][C:12]=3[N:27]=2)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C=NC1CCCCC1
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC3CCCCC3)nc2n1
Yield: 71.9 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 53 in DMF (15 mL) was reacted with 60% sodium hydride suspension (0.092 g) and cyclohexyl isocyanate (0.289 g) according to the general procedure of Example 54 to give 0.927 g of the title compound, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=558, 433.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[CH3:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: C#CC(=O)OC
Reactant: Cc1cccc(C(=O)Cc2nc3c([nH]2)CCCC3)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(C(=O)c2ccc(=O)n3c4c([nH]c23)CCCC4)c1

Procedure:
The compound is prepared as described in example 25 with 200 mg (0.63 mmol) of 1-(3-Methylphenyl)-2(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XXXXVIII, 68.4 mg (1.27 mmol) of sodium methylate and 53.2 mg (0.63 mmol) methyl propiolate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:28][CH3:29])=[C:13]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:17]([N:18]=[CH:32][N:33]([CH3:35])[CH3:34])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:28][CH3:29])=[C:13]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCCN1CCOCC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N=CN(C)C)cc2cc1OCCN1CCOCC1

Procedure:
A mixture of 0.69 g (1.7 mmol) of 3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic acid tert-butyl ester and 2.4 mL of N,N-dimethylformamide dimethyl acetal in 7.0 mL of toluene is heated under reflux for 1.5 hours. The solvent is evaporated and the residue is dried on high vacuum to yield 3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)naphthalene-2-carboxylic acid tert-butyl ester as purple white foam.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH3:12].F>>[CH3:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:2]([NH2:3])=[S:1]
Reactant: Cc1ccccc1C
Reactant: N#C[S-]
Agent: F
Agent: [K+]
Product: Cc1ccc(C(N)=S)cc1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
At a temperature as indicated in Example 1, 59 g of potassium thiocyanate (0.6 mol) and 79.5 g of o-xylene (0.75 mol) are stirred with 0.5 l of 98% hydrofluoric acid. and the mixture is then stirred for 10 hours at room temperature. Subsequently, the batch is poured onto ice, the precipitated product is suction-filtered after having been stirred for one-half hour, and the greater part of the non-reacted o-xylene (15 g) is separated from the still moist filter cake by steam distillation. The distillation residue is subsequently suction-filtered and dried. The yield of dimethylthiobenzamide having a melting point of 120° - 125° C is 99 g and therefore quantitative, relative to the potassium thiocyanate used.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[CH2:47]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:13]([O:12][C:10]([CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:47]=[CH:46][C:45]([O:49][CH2:50][CH3:51])=[O:48])=[CH:3][CH:4]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)CSc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1ccc(SCC(=O)OC(C)(C)C)cc1
Yield: 73.7 %

Procedure:
3.46 g of t-butyl [(4-bromophenyl)thio]acetate was mixed with 8 ml diisopropylethylamine, 0.6 g of triphenylphosphine, 5.2 ml ethyl acrylate and 35 ml acetonitrile to form a solution. 0.26 g of palladium acetate was further added to the solution and refluxed under a stream of argon for 44 hours. The reaction mixture was extracted with ethyl acetate, washed with water. The aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated and purified via column chromatography on silica gel (ethyl acetate:hexane=1:20) to give ethyl 4-[[(t-butoxycarbonyl)methyl]thio]cinnamate (2.7 g, 73.7%).
Reaction SMILES: C([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7]C1(C)C)(=O)CC.Cl.[OH-].[Na+].C(Cl)Cl>O>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([C@@H:8]([OH:7])[C@H:9]([NH2:5])[CH2:10][F:11])=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: CCC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1

Procedure:
(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl; R2, R3 and R4 are methyl) (50.0 g, 0.1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90 to 100° C. over about 1 hour. Adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (500 mL) yields (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (Compound Xa) in solution. Addition of triethylamine (16.9 g, 0.1670 moles) and dichloroacetyl chloride (24.6 g, 0.1670 moles) at 20-30° C. for 4-6 hours then removal of methylene chloride by distillation and replacement by toluene (350 mL) and water (100 mL) precipitates the product. Filtration, washing with water (150 mL) and toluene (150 mL) then drying yields (1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol (Florfenicol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Cl:12]C1C=CC=C(C(OO)=[O:20])C=1.Cl.C(OCC)C>ClCCl.CO>[ClH:12].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1ccc2cnccc2c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(Br)ccc2c1
Yield: 90.8 %

Procedure:
To a stirred solution of 13.2 g of 6-bromoisoquinoline (Tyson, F. L., J. Am. Chem. Soc. 61, 183 (1939)) in 250 mL of dichloromethane at room temperature was added in portions 16.2 g of m-chloroperbenzoic acid (purity 70%). After stirring the mixture for one hour 200 mL of methanol was added and the bulk was reduced to 150 mL. A hydrogen chloride solution in methanol (100 mL, 0.75 M) was added and after slightly heating a clear solution was obtained. Diethylether (250 mL) was added to this solution and cooled in an ice bath. The hydrochloride salt precipitated and was isolated by filtration to give 15 g of 1a. M.p. 194-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](=O)[C:14](=[CH:17][N:18](C)C)[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.[NH2:25]N>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]3=[N:25][NH:18][CH:17]=[C:14]3[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)C(=CN(C)C)CCC2
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2c1-c1n[nH]cc1CCC2

Procedure:
The title compound is prepared in analogous fashion to Example 8 using 5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester and hydrazine acetate. The crude product mixture is carried into the next step without purification. Electrospray mass spectrum: m/z 246 [M+1]; 1H NMR (DMSO-d6, 300 MHz) δ>13.0 (br s, 1H), 11.65 (br s, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.91 (m, 2H), 2.76 (m, 2H), 1.84 (m, 2H) 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.N1(C([O-])=O)CCNCC1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:2]2[N:3]=[C:4]([O:12][C@@H:13]([C@@H:15]3[CH2:16][C:17](=[O:20])[NH:18][CH2:19]3)[CH3:14])[C:5]3[N:6]([N:8]=[CH:9][C:10]=3[CH3:11])[CH:7]=2)[CH:26]=[CH:25][C:24]=1[N:38]1[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]1
Reactant: Cc1cnn2cc(Cl)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])N1CCNCC1
Product: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the procedure of Example 5.55, beginning with (R)-4-((R)-1-(6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.54 (25.3 mg, 0.086 mmol) and tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate 7.08 (44 mg, 0.105 mmol), tert-butyl 4-(2-methoxy-4-(3-methyl-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate 5.59 (35 mg) was synthesized.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:11][Si:12]([CH3:16])([CH3:15])[C:13]#[CH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][Si:12]([C:13]#[C:14][C:3]1[CH:4]=[C:5]2[N:10]=[CH:9][NH:8][C:6]2=[N:7][CH:2]=1)([CH3:16])[CH3:15]
Reactant: Brc1ccc2nc[nH]c2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc2[nH]cnc2c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.2 g (6.1 mmol) 5-bromo-3H-imidazo[4,5-B]pyridine and 1.2 mL (8.4 mmol) 1-trimethylsilyl-ethyne using 34 mg (0.18 mmol) CuI, 159 mg (0.61 mmol) triphenylphosphine, 128 mg (0.18 mmol) PdCl2(PPh3)2 and 10.1 mL (72.7 mmol) triethylamine in 10 mL dry THF. The formed precipitate is filtered off and the product is purified by RP-HPLC using a ACN/H2O gradient. Yield: 606 mg (46%)