Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.CC(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([NH:61][C:62](=[O:70])[CH2:63][CH2:64][O:65][C:66]([CH3:69])([CH3:68])[CH3:67])[CH:59]=2)[CH:54]=[C:53]1[C:71](O)=[O:72])=O)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:71]([C:53]2[NH:52][C:60]3[C:55]([CH:54]=2)=[CH:56][CH:57]=[C:58]([NH:61][C:62](=[O:70])[CH2:63][CH2:64][O:65][C:66]([CH3:68])([CH3:67])[CH3:69])[CH:59]=3)=[O:72])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
HATU (0.090 g, 0.237 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.0491 g, 0.158 mmol), 1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-({3-[(1,1-dimethylethyl)oxy]propanoyl}amino)-1H-indole-2-carboxylic acid (0.048 g, 0.158 mmol) and diisopropylethylamine (0.041 mL, 0.237 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.055 g, 58%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (s, 1H), 9.81 (s, 1H), 8.89 (t, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.39-7.53 (m, 4H), 7.36 (t, 1H), 7.03-7.12 (m, 2H), 4.52 (d, 2H), 3.57 (t, 2H), 2.36-2.49 (m, 2H), 1.10 (s, 9H). ES MS: m/z 597 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([NH:13][C@H:14]2[C@H:18]([OH:19])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH:3]=1.C(OC(C)C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([NH:13][C@@H:14]2[CH2:15][NH:16][CH2:17][C@H:18]2[OH:19])[CH:3]=1
Reactant: Cc1ccc2nc(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3O)cc(C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: Cc1ccc2nc(N[C@@H]3CNC[C@H]3O)cc(C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-chloro-4,6-dimethylquinoline (0.40 g), Pd2(dba)3 (0.095 g), (±)-BINAP (0.20 g), (S)-t-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (0.51 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.60 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the solids were washed with ethyl acetate and diisopropyl ether to obtain (3R,4R)-t-butyl 3-(4,6-dimethylquinolin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (0.39 g). (2) (3R,4R)-t-Butyl 3-(4,6-dimethylquinolin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (0.39 g) was dissolved in 4 M HCl in 1,4-dioxane (5 mL), and the mixture was stirred at room temperature for 2 h. To the reaction suspension was added diisopropyl ether, the mixture was stirred, and then the solids were collected by filtration to obtain (3R,4R)-4-(4,6-dimethylquinolin-2-ylamino)pyrrolidin-3-ol di hydrochloride (0.32 g).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)=[S:16])=[CH:9][C:8]=1[Cl:28])C.O1CCCC1.[OH-].[Na+].Cl>CO>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[S:16])[NH:14][C:10]2[CH:11]=[C:12]([Cl:13])[C:7]([O:6][CH2:5][C:4]([OH:29])=[O:3])=[C:8]([Cl:28])[CH:9]=2)=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)COc1c(Cl)cc(NC(=S)Nc2ccc(NC(C)=O)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCC(=O)O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid ethyl ester (0.29 g) in a 1:1 mixture of tetrahydrofuran and methanol (4 mL) is added 1N aqueous sodium hydroxide (2 mL) and the mixture is stirred for approximately 2 hours at room temperature. The solution is then poured into 2 M aqueous hydrochloric acid (5 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([OH:20])=O)[CH3:2].[CH:21]([NH:24][NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:29][CH:28]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:24]([CH:21]([CH3:23])[CH3:22])[NH:25][C:26](=[O:38])[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:31][CH:32]=2)=[O:20])=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:14]=1
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Reactant: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccc(OCCOC)cc1)C(C)C
Yield: 7.8 %

Procedure:
A solution of (2′-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (38 mg, 0.1395 mmol), and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.053 ml, 0.38 mmol), HOBT (20 mg, 0.152 mmol), and EDCI (29 mg, 0.152 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white solid (5 mg, 7%). MS m/e 509.42 (M+H+)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a suspension of sodium hydride in DMF (50 ml) at 0° C. was added dropwise a solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55.5 mmol) and benzyl bromide (7.93 ml, 66.7 mmol) dissolved in DMF (100 ml). The mixture was stirred at room temperature for 16 hours, cooled to 0° C., quenched with aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with aqueous ammonium chloride (50 ml), brine (3×60 ml), dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from hexane-ethyl acetate to give the title compound (13.7 g, 91%) as a white solid.
Reaction SMILES: C[Si]([Br:5])(C)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([Cl:25])[C:14]=1[C:15]1[S:16][C:17]2[C:18](Cl)=[N:19][CH:20]=[CH:21][C:22]=2[N:23]=1)[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:14]3[C:7]([Cl:6])=[CH:8][C:9]([C:10]#[N:11])=[CH:12][C:13]=3[Cl:25])=[N:23][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC#N
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Temperature: 90 °C
Yield: 96.1 %

Procedure:
Trimethylsilylbromide (0.23 mL, 1.74 mmol) was added to a stirred solution of 3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridine-2-yl)-benzonitrile (295 mg, 0.87 mmol) in propionitrile (11 mL) and the mixture heated at 90° C. for 48 hours. The reaction mixture was allowed to cool and poured onto a mixture of saturated aqueous potassium carbonate solution and ice. DCM was added and the organic phase was separated, dried over Na2SO4 and concentrated to dryness under reduced pressure to give the desired compound as a white solid (322 mg, 96% yield). 1H NMR (300 MHz, CDCl3): δ 8.53 (d, J=5.5 Hz, 1H), 8.03-8.00 (m, 1H), 7.80 (s, 2H). LCMS (Method D): RT=4.04 min, m/z: 386 [M+H+].
Reaction SMILES: [CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:30])=[O:29])[CH:23]=2)[NH:5][N:4]=1)[CH3:2].[OH:31]OS([O-])=O.[K+]>CO.O>[CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:30])(=[O:31])=[O:29])[CH:23]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCc1n[nH]c(CCOc2cccc(S(C)=O)c2)c1Oc1cc(C#N)cc(C#N)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1n[nH]c(CCOc2cccc(S(C)(=O)=O)c2)c1Oc1cc(C#N)cc(C#N)c1
Yield: 34.4 %

Procedure:
To a stirred solution of the sulfoxide from Example 5 (34 mg, 0.08 mmol) in methanol (1 ml) was added a solution of oxone (49 mg, 0.08 mmol) in water (1 ml). After 2 hours the reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (5 ml) and water (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (100:0, 99:1 then 98:2, by volume) to give the title compound as a colourless oil (12 mg).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]1=[O:13].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CCO>[O:13]=[C:3]1[CH:2]([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)C1CCC(Br)C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCC(Sc2ccccc2)C(=O)C1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of ethyl 4-bromo-3-oxocyclohexanecarboxylate (3.73 g, 15 mmol) in EtOH (30 mL) at 80° C. was added a solution of benzenethiol (1.65 mL, 15 mmol) and NaOH (0.6 g, 15 mmol) in EtOH (100 mL). The suspension was stirred for 1 hour, then was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with water then brine, then was dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel afforded 2.56 g (61%) of the title compound as a yellow oil: MS (−) 277 (M−H)−.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:17])[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[S:4][CH:3]=1.O1CCO[CH2:20][CH2:19]1>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>[Cl:17][C:8]1[N:9]=[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:4][CH:3]=[C:2]([CH:19]=[CH2:20])[C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2scc(Br)c2n1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1csc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 100 °C
Yield: 39.5 %

Procedure:
4-(7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (3.55 g, 10.6 mmol), (2-Ethenyl)tri-n-butyltin (3.41 mL, 11.7 mmol), Pd(PPh3)4 (613 mg, 0.53 mmol), and 1,4-Dioxane (30 mL, 400 mmol) were combined in a sealed tube and heated at 100° C. 19.5 h. Complete reaction was confirmed by LCMS. Concentrated in vacuo and purified by silica gel chromatography (0 to 50% ethyl acetate/heptanes) on the CombiFlash® Rf system and concentrated in vacuo to give 4-(2-chloro-7-vinylthieno[3,2-d]pyrimidin-4-yl)morpholine (1.18 g, 39.5% yield)
Reaction SMILES: [CH:1]1([C:7]2([NH2:14])[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH3:31])[C:18]=1[C:19](Cl)=[O:20]>>[CH:1]1([C:7]2([NH:14][C:19](=[O:20])[C:18]3[C:22]([S:30][CH3:31])=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:17]=3[O:16][CH3:15])[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: CN1CCCC(N)(C2CCCCC2)C1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(C2CCCCC2)CCCN(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-3-cyclohexyl-1-methyl-piperidin-3-ylamine (Example A.11) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B6). MS (m/e): 445.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:17](=[O:19])[CH3:18]
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(C)=O

Procedure:
To a solution of 10-methoxyharmalan (1 mmol) in pyridine (2 ml) is added acetic anhydride (1.1 eq) . After acid hydrolysis and extraction with ethyl acetate, the crude product is flash-chromatographed (eluent: EtOAc/pet. ether; 50/50). The 1-methylene-2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline elutes off first.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=2)[N:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:18]S(O)(=O)=O>>[C:8]([C:7]1[CH:6]=[N:5][N:4]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:3]2[C:2]=1[Cl:1])(=[O:18])[NH2:9]
Reactant: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a round bottom flask was added concentrated H2SO4 (100 mL) followed by ethyl 4-chloro-3-cyanopyrrolo[1,2-b]pyridazine-6-carboxylate (10 g, 40 mmol). The reaction was stirred at room temperature under nitrogen overnight. The reaction mixture was poured onto ice cold saturated sodium carbonate solution. The aqueous solution was extracted with EtOAc (4×) and the combined organic layer was concentrated to yield 7 g (70%) of the title compound as a yellow solid. HPLC (condition S): retention time=8.04 min. LCMS (condition A): m/z=268.0+ve. 1H NMR (400 MHz, CDCl3) δ ppm: 8.49 (1H, d, J=1.6 Hz), 8.40 (1H, s), 8.08 & 7.98 (1H, two br s), 7.12 (1H, d, J=1.6 Hz), 4.34 (2H, q, J=7.2 Hz), 1.34 (3H, t, J=7.2 Hz).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[N:13])[C:9]2[N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[S:16][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].Cl>C[O-].[Na+].CO.O>[C:17]([C:15]1[S:16][C:8]2[C:7]([OH:21])=[C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])[N:11]=[C:10]([C:12]#[N:13])[C:9]=2[N:14]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1nc(C#N)c2nc(C(C)(C)C)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2s1
Yield: 53.4 %

Procedure:
A suspension of 2-tert-butyl-4-cyano-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (85 mg, 0.28 mmol) and glycine (188 mg, 2.5 mmol) in 4.4 mL of 0.5 N NaOMe in methanol was heated at reflux temperature for 25 h. The reaction mixture was diluted with water, acidified with 1 N HCl, and extracted with ethyl acetate. The organic fraction was concentrated to a residue and purified by reverse phase chromatography on a C-18 column, eluting the desired product with a gradient of 10-90% acetonitrile in water+0.1% formic acid. The lyophilized material fractions provided 50 mg of white solid. MS (ESI−): m/z 333.0 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2) as starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Cl-].[Cl-].[Al+3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[O:31][CH3:32])[CH:21]=[CH:22][CH:23]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:25]([O:31][CH3:32])=[CH:26][CH:27]=[C:28]([C:8]([C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:9])[C:29]=2[F:30])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(F)c1-c1cccc(Cl)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 4-nitro-benzoyl chloride (1900 mg, 10.2 mmol) in nitrobenzene (6 mL) was added aluminum trichloride (1360 mg, 10.2 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 h, cooled to 0° C., and 3′-chloro-6-fluoro-2-methoxy-biphenyl (2.01 g, 8.5 mmol) in nitrobenzene (1 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred 24 h. The reaction mixture was cooled to −10° C. and quenched with ice-water (50 mL), extracted with ethyl acetate (2×25 mL), washed with water (2×10 mL), saturated aqueuos sodium bicarbonate (10 mL), brine (30 mL), and dried over Na2SO4. After filtration and removal of solvent, the crude was purified by crystallization from ether-hexane to give I-133 (3.00 g, 91% yield).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[C:9]([Br:11])[N:10]=1>CO>[Br:11][C:9]1[N:10]=[C:5]([O:2][CH3:1])[C:6]([NH2:12])=[N:7][CH:8]=1
Reactant: C[O-]
Reactant: Nc1ncc(Br)nc1Br
Agent: [Na+]
Solvent: CO
Product: COc1nc(Br)cnc1N
Temperature: 25 °C

Procedure:
A 30% w/w solution of NaOMe in MeOH (8.4 mL, 44.8 mmol) was added to a stirring suspension of 3,5-dibromo-2-aminopyrazine (10 g, 39.5 mmol) in dry MeOH (40 mL). The reaction mixture was heated to reflux and maintained for 3 h. The reaction was allowed to cool to rt and concentrate to 1/3 volume. The reaction was then partitioned between DCM and saturated aqueous NaHCO3 solution. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution (3×). The combined aqueous portions were back extracted with DCM (3×). The combined organic portions were washed with brine, dried (Na2SO4), and concentrated to provide 8.1 g of 5-bromo-3-methoxypyrazin-2-amine: 1H NMR (300 MHz, CDCl3): 7.64 (s, 1H), 4.79 (br s, 2H), 4.01 (s, 3H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@@H:31](OS(C)(=O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: Clc1ccc(Nc2ccccc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
Sodium hydride (0.36 g, 60% in oil) was added to 20 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 2.0 g of 3,4-dichlorophenyl-phenylamine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 1.5 g of 3(R)-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution, and the reaction solution was then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.13 g of light brown amorphous solid 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine 1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)[C:12](Cl)=[O:13]>ClC(Cl)C>[C:1]1([CH2:7][C:8]([N:10]=[C:12]=[O:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: O=C=NC(=O)Cc1ccccc1
Reaction time: 0.08 h

Procedure:
To a suspension of 2-phenylacetamide (68 mg, 0.5 mmol) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.0 mmol). The suspension dissolved quickly and a new suspension formed. LC/MS analysis of the reaction mixture after 5 min indicated none of the desired product had formed. The mixture was warmed to 80° C., LC/MS after 30 min indicated a small amount of product. The reaction was heated at 70° C. for 2 days and became mostly clear. LC/MS analysis indicated mostly product. The mixture was shaken and heated at 80° C. for another 4 h. Almost all of the yellow solid on the walls of the reaction vessel had dissolved. The mixture was concentrated in vacuo. The residue dissolved in dichloroethane (1.5 mL), concentrated, and redissolved in dichloroethane (2 mL). The resulting 0.25 M solution was used without further purification.