Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[N:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:19]3[N:20]=[N:21][CH:22]=[N:18]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2ncnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Yield: 10.7 %

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.34 g), 1-[4-(2H-2-tetrazolyl)-phenyl]-2(1H,3H)-imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to 1-methyl-2-pyrrolidone (100 ml), and the mixture was heated at 80° C. for 18 hours with stirring. The reaction solution was cooled, diluted with * ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/acetone=1/1) to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 40; 0.494 g) as a colorless crystalline powder.
Reaction SMILES: [CH:1]([C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2].C1COCC1.[C:21]1([CH3:29])[CH:26]=[CH:25][CH:24]=[C:23]([Mg]Cl)[CH:22]=1.[NH4+].[Cl-]>O>[OH:2][C@H:1]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:29])[CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Cc1cccc([Mg]Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc([C@@H](O)[C@H]2[C@@H](c3ccccc3)CC(=O)N2C)c1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a 0° C. solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 74 mg, 0.4 mmol) in anhyd. THF (5 mL) was added a solution of m-tolyl magnesium chloride (1M in THF, 0.5 mL, 0.5 mmol, 1.25 equiv). The reaction mixture was stirred for 1 h, then treated with a saturated NH4Cl solution and water. The resulting mixture was extracted with EtOAc, dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated (Et2O/hex) to give (±)-(4R*,5R*)-5-[(1R*)hydroxy(3-methylphenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one (82 mg, 77%): mp 163-165° C.; TLC (EtOAc) Rf 0.45.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH2:11]Br)=O)=[CH:5][CH:4]=1.[NH:13]=[C:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH:11]=2)=[CH:5][CH:4]=1
Reactant: N=C1CCCN1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cn3c(n2)CCC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.8 g (29.7 mmoles) of 2-bromo-4-methoxyacetophenone in 50 ml of CHCl3 was added a solution of 5 g (59.4 mmoles) of 2-iminopyrrolidine in 30 ml of CHCl3 with chilling. After 4 hours of stirring at 25° C., the solvent was removed in vacuo. The residue was dissolved in water, the pH adjusted to 2.5 and the solution heated on a steam bath under argon atmosphere for 8 hours. The cooled solution was adjusted to pH 6. The resulting precipitate, filtered, washed with water and dried in vacuo to afford the titled compound, mp 116°-117.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:27])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]#[C:19][CH2:20][N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:27])[N:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH2:16][CH2:17]2)[CH3:11])=[CH:6][CH:7]=1
Reactant: CCN(CC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1)CCO
Agent: [Pt]
Solvent: CO
Product: CCN(CCO)CCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
A suspension of 65 mg (0.165 mmol) of trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-prop-1-ynyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester in 5 ml MeOH and 7 mg Pt/C 10% was hydrogenated (1 atm) for 16 h. The reaction was filtered (Celite) and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (9:1) gave 21 mg (32%) of trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-propyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 397 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCOC(C)=O.CCCCCCC>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:15][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(=O)C[C@H]1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(S(=O)(=O)OC2=CC(=O)N(C(=O)OC(C)(C)C)[C@H](C(=O)OCc3ccccc3)C2)cc1

Procedure:
Similar to example 24c, 9.43 g of (2S)-4,6-dioxo-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester [176436-10-5] are reacted with p-toluene sulfonyl chloride to afford the title compound as a yellow oil Rf=0.64 (EtOAc-heptane 1:1); Rt=5.20.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:30][CH:31]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: C=CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-prop-2-enoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-prop-2-enoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: BrCC1C=CC(C(OC(C)(C)C)=O)=C(Cl)C=1.FC(F)(F)CN.[Cl:23][C:24]1[CH:36]=[C:35]([CH2:37][NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:34]=[CH:33][C:25]=1[C:26]([O:28]C(C)(C)C)=[O:27].Cl>CS(C)=O.O1CCOCC1>[Cl:23][C:24]1[CH:36]=[C:35]([CH2:37][NH:38][CH2:39][C:40]([F:41])([F:42])[F:43])[CH:34]=[CH:33][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccc(CNCC(F)(F)F)cc1Cl
Agent: CC(C)(C)OC(=O)c1ccc(CBr)cc1Cl
Agent: Cl
Agent: NCC(F)(F)F
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: O=C(O)c1ccc(CNCC(F)(F)F)cc1Cl

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CC(C)([O-])C.[Na+]>C1(C)C=CC=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]>[CH2:13]([NH:19][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCNc1cccc(C2OCCO2)c1
Yield: 94.6 %

Procedure:
According to the general procedure B, 2-(3-bromophenyl)-1,3-dioxolane (115 mg, 0.50 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 100° C. to give the title compound (118 mg, 94%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.19 (t, 1H, J=7.8 Hz), 6.81 (d, 1H, J=6.9 Hz), 6.74 (s, 1H), 6.61 (m, 1H), 5.77 (s, 1H), 4.13 (m, 2H), 4.03 (m, 2H), 3.55 (bs, 1H), 3.13 (t, 2H, J=6.9 and 7.2 Hz), 1.62 (m, 2H), 1.45-1.33 (m, 6H), 0.92 (t, 3H, J=6.0 and 6.9 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 148.53, 138.85, 129.21, 115.07, 113.48, 110.31, 103.88, 65.15, 43.98, 31.58, 29.43, 26.78, 22.59, 14.01. GC/MS (EI): m/z 249 (M+). Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found: C, 72.19; H, 9.43; N, 5.70.
Reaction SMILES: [SH2:1].[C:2]([N:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][NH:6]1)#[N:3].[OH-].[Na+]>O>[C:2]([N:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][NH:6]1)(=[S:1])[NH2:3]
Reactant: S
Reactant: N#CN=C1NCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=S)N=C1NCCCN1
Temperature: 45 °C
Reaction time: 27.5 h
Yield: 94 %

Procedure:
Hydrogen sulphide is first passed into a solution of 190 g (1.53 mols) of 2-(N-cyanimino)-hexahydropyrimidine (a) in 760 ml of water at 75° C. for 12 hours; and then at 65°-70° C. for another 25-30 hours. (On the second day, some of the precipitate no longer dissolves). The suspension is then warmed to 45° C. and 46 ml of 40% strength NaOH are added. Stirring is continued for 30 minutes and the residue is ground and filtered off with suction. After drying, 228 g (94%) of product are obtained. Melting point=187°-189° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH:19]1[C:24](=[O:25])[CH2:23][NH:22][CH2:21][C:20]1=[O:26].C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:22]2[CH2:23][C:24](=[O:25])[NH:19][C:20](=[O:26])[CH2:21]2)[CH:7]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: O=C1CNCC(=O)N1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Cl)cc(N2CC(=O)NC(=O)C2)n1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 32 h
Yield: 58.8 %

Procedure:
182 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1) and 80 mg of piperazine-2,6-dione were dissolved in 2 ml of tetrahydrofuran and 2 ml of N,N-dimethylformamide, and 122 μl of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 80° C. for 32 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 136 mg of the objective compound as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[N:11]=[CH:10][NH:9][C:8]=2[CH:12]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[N:11]=[CH:10][NH:9][C:8]=2[CH:12]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]cnc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc2[nH]cnc12
Yield: 102.4 %

Procedure:
Methyl 6-nitro-1H-benzimidazole-4-carboxylate (304 mg) was suspended in MeOH (10 mL), the suspension was added with 5% palladium on carbon (30 mg), and stirred under hydrogen (1 atm) atmosphere. The catalyst was filtered off on celite and washed with MeOH, and the mother liquor was concentrated in vacuo to obtain the titled compound (269 mg) as pale yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:21])[CH:15]=[C:16]([NH2:20])[O:17][CH2:18][CH3:19]>C(O)(C)C>[CH3:12][O:13][C:14]([C:15]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:15]([C:14]([O:13][CH3:12])=[O:21])[C:16]([O:17][CH2:18][CH3:19])=[N:20][C:16]=1[NH2:20])=[O:21]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(N)=CC(=O)OC
Solvent: CC(C)O
Product: CCOC1=NC(N)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C1C(=O)OC

Procedure:
Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde and 14.5 g of 3-amino-3-ethoxyacrylic acid methyl ester in 40 ml of alcohol for 6 hours, 2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid dimethyl ester of melting point 163°C (isopropanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][N:28]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[N:29]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[CH:30]=[N:29][N:28]([CH2:27][C:26]4[CH:42]=[CH:43][C:23]([F:22])=[CH:24][CH:25]=4)[CH:32]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccc(F)cc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Yield: 38.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (700 mg, 1.46 mmol) was coupled with 1-(4-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 7) (554 mg, 1.83 mmol) in sodium carbonate (466 mg, 4.4 mmol), bis(triphenylphosphine) palladium(ii)dichloride (51 mg, 0.073 mmol) and toluene/ethanol/water (20/8/2 ml) to afford 300 mg (38.9% yield) of the pure product after column purification using 20% ethyl acetate in hexane as eluent. MS: m/z=526.7 (M+1).
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15][N:14]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([CH2:23][N:20]1[CH2:21][CH2:22][NH:11][CH2:12][CH2:13][N:14]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CCN(CC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of 7 (8.52 g, 12.74 mmol) in ethanol (130 mL) was added 10% Pd/C (2.6 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL). The combined filtrate was evaporated in vacuo to give an oily residue which was triturated with Et2O to provide an off-white solid 8 (4.85 g, 97% yield).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[C:9]([NH:14][C:15](=O)OC(C)(C)C)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:7].Cl.[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C.CN(C=O)C>[CH3:7][C:6]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:14][CH:15]=1
Reactant: CCc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Normal-butyllithium (2.69 M, 118.7 mL) was dropwise added to a solution of compound (40a) (32.4 g) in THF (500 mL) at an internal temperature of −30 to −10° C., followed by stirring at 0° C. for 30 min. Subsequently, a solution of DMF (11.18 g) in THF (50 mL) was added to the reaction solution at an internal temperature of −40° C., followed by increasing the temperature to room temperature. Then, 6 N hydrochloric acid (200 mL) was added to the reaction solution, followed by stirring at 60° C. for 2 hr. After cooling, ethyl acetate (200 mL) and water (100 mL) were added to the reaction solution for distribution. The aqueous layer was added to sodium hydroxide (4 M, 300 mL), and pH was adjusted to 12, followed by stirring for 1 hr. The precipitate was collected by filtration, washed by sprinkling water, and dried under reduced pressure to obtain compound (40b) (16.52 g, 86%) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:6]=1[CH3:5])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(N)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.98 ml (27.78 mmol) of acetyl chloride were added, with stirring, to a solution of 3.161 g (25.26 mmol of 2-methyl-3-fluoroaniline and 3.87 ml (27.78 mmol) of triethylamine in 50 ml of DCM at 0° C. The solution was allowed to warm up to ambient temperature and was stirred for 1 hour. The solution was washed with water (3 times 50 ml), the product was dried with MgSO4 and the solvent was removed under reduced pressure. After recrystallization from a mixture of mineral oil/ethyl acetate (EtOac), 3.844 g (91%) of the title compound were obtained in the form of white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[OH-].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(ccn4C)c3)c(Cl)c2Cl)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc2cc(Sc3ccc(/C=C/C(=O)N4CCC(C(=O)O)CC4)c(Cl)c3Cl)ccc21

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with ethyl ester from Example 339, and KOH with NaOH, to give a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 1.31-1.53 (m, 2H), 1.62-1.76 (m, 2H), 1.94-2.09 (m, 1H), 2.88 (brt, J=10.5 Hz, 1H), 3.13 (brt, J=10.5 Hz, 1H), 3.86 (s, 3H), 3.93 (br d, J=13.2 Hz, 1H), 4.09 (br d, J=13.2 Hz, 1H), 6.41 (d, J=8.7 Hz, 1H), 6.53 (dd, J=0.9, 3.0 Hz, 1H), 7.04 (d, J=15.3 Hz, 1H), 7.32 (dd, J=2.1, 8.7 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.69 (d, J=15.3 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H). MS (ESI+) (M+H) at m/z 489, 491, 493. Anal. Calcd for C24H21Cl2N2NaO3S.0H2O: C, 56.37; H, 4.14; N, 5.48. Found: C, 56.44; H, 4.38; N, 5.20.
Reaction SMILES: CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([CH:45]([CH2:57][CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[C:46]([NH:48][C:49]2[S:50][C:51]([C:54](O)=[O:55])=[CH:52][N:53]=2)=[O:47])=[CH:41][CH:40]=1)(=[O:38])=[O:37].Cl.[CH3:65][NH:66][O:67][CH3:68]>CN(C=O)C>[CH3:68][O:67][N:66]([CH3:65])[C:54]([C:51]1[S:50][C:49]([NH:48][C:46](=[O:47])[CH:45]([C:42]2[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:44][CH:43]=2)[CH2:57][CH:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:53][CH:52]=1)=[O:55]
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
NEt3 (647 μL, 4.64 mmol) and BOP (976 mg, 2.21 mmol) were added to a stirred solution of 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylic acid (EXAMPLE 127, 968 mg, 2.21 mmol) in anhydrous DMF (30 mL). After 5 min, N,O-dimethylhydroxylamine hydrochloride (237 mg, 2.43 mmol) was added, then the mixture was stirred at 20° C. for 18 h. The solvents were removed in vacuo, then the residue was dissolved in EtOAc (75 mL). The EtOAc solution was washed with saturated aqueous Na2CO3 (40 mL), 2M HCl (40 mL), and brine (40 mL), before being dried (MgSO4). Filtration and solvent evaporation provided the title compound: RTB=1.27 min; m/z (ES+)=482.0 [M+H]+.