Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Br:7][C:8]1[CH:9]=[C:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([O:20][CH3:21])=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([O:20][CH3:21])=[C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:18][CH2:19]2)[CH:13]=1
Reactant: COCC(=O)Cl
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC(=O)N1CCN(c2cc(Br)cc(C(C)(C)C)c2OC)CC1
Reaction time: 1 h

Procedure:
Methoxyacetyl chloride (0.28 ml) was added to a solution of 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (850 mg) and triethylamine (0.73 ml) in methylene chloride (12 ml) while cooling on ice, the mixture was brought to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, the insoluble portion was filtered off, and the concentrated residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (730 mg) as light red crystals (70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: Cc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1CCOCC1
Reaction time: 6 h
Yield: 101 %

Procedure:
The above general procedure was followed using 2-bromotoluene (171 mg, 1.10 mmol) and morpholine (87 mg, 1.00 mmol) with 1 mol % Pd(OAc)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 6 hours, the reaction mixture was adsorbed onto silica gel and chromatographed using 5% ethyl acetate/hexanes to give 179 mg (>99%) of N-(2-methylphenyl)morpholine. 1H NMR (500 MHz, CDCl3) δ 7.20 (d J=7.4 Hz, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.03 (d, J=7.4 Hz, 1H), 7.01 (d, J=7.4 Hz, 1H), 3.86 (t, J=4.5 Hz, 4H), 2.92 (t, J=4.5 Hz, 4H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 151.4, 132.7, 131.2, 126.7, 123.5, 119.0, 67.5, 52.4, 17.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-])=O)=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[ClH:23]>[C].[Pt].C1(C)C=CC=CC=1>[ClH:23].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([NH:12][CH3:13])[C:10]=1[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNc1cccc(OCc2ccccc2)c1N
Reaction time: 0.5 h
Yield: 85 %

Procedure:
0.80 g of 5% platinum carbon (dry) was added to a toluene (80 mL) suspension of 3-benzyloxy-N-methyl-2-nitroaniline (7.19 g, 27.8 mmol), and catalytic hydrogenation reaction was performed under ordinary pressure. The reaction solution was filtered to remove a catalyst, and the catalyst was washed with toluene (10 mL). The washing liquid was added to the precedent filtrate. A 1N hydrochloric acid ethanol solution (28 mL, 28.0 mmol) was added to the mixture under ice cooling, and the mixture was stirred under the same temperature for 30 minutes. The solvent was distilled off under reduced pressure at 20° C. or less. Precipitated crystals were collected by filtration, washed with toluene (15 mL), and dried at 40° C., thereby obtaining 6.30 g of an orange, crystal target compound (yield: 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([O:13][C:14]([N:16]1[CH2:19][C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([N:4]2[CH2:5][CH2:6][O:7][C:2]([CH3:8])([CH3:1])[CH2:3]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC1(C)CNCCO1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCOC(C)(C)C2)C1
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 2,2-dimethylmorpholine (260 mg, 2.26 mmol) and 3-oxoazetidine-1-carboxylic acid tert-butyl ester (464 mg, 2.71 mmol) in DCE (15 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (957 mg, 4.52 mmol). The resulting mixture was stirred for 16 h, then diluted with DCM and washed with H2O. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-40%) affording the title compound as an oil (492 mg, 81%). 1H NMR (CDCl3, 300 MHz): δ 3.95-3.85 (m, 2H); 3.80-3.71 (m, 4H); 3.07-2.88 (m, 1H); 2.32-2.22 (m, 2H); 2.14-2.06 (m, 2H); 1.44 (s, 9H); 1.25 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].CN(C1C=CC=CN=1)C>CN(C)C=O.O>[CH3:28][S:29]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)(=[O:31])=[O:30]
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3cc(O)ccc3c12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc2c(c1)[nH]c(=O)c1c3ccc(OS(C)(=O)=O)cc3oc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In dry N,N-dimethylformamide was dissolved 500 mg of 3,9-dihydroxy-5H-benzofuro[3,2-c]quinolin-6-one. To the solution were added successively 1.3 ml of triethylamine, 0.72 ml of methylsulfonyl chloride and 10 mg of -dimethylaminopyridine, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the precipitates were collected by filtration, washed with water and ether, and dried to obtain 725 mg of 3,9-bis(methylsulfonyloxy)-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2ncc3c(n2)C(OS(C)(=O)=O)CCC3)ccc1-n1cnc(C)c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(n2)C(N2CCCC2)CCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a suspension of methanesulfonic acid 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-5,6,7,8-tetrahydro-quinazolin-8-yl ester (61 mg, 0.14 mmol) in tetrahydrofurane (1.4 mL) was added under nitrogen at 0° C. pyrrolidine (20 mg, 0.28 mmol) and triethyl amine (29 mg, 0.28 mmol). The reaction was stirred at room temperature over night, heated to reflux for 2 hours. A few drops of dimethylformamide were added and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, dissolved in water and extracted twice with ethyl acetate. The combined organic layers were washed with dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane/methanol/concentrated aqueous ammonia (19:1:0.2 v/v/v) as eluent to yield the title compound (24 mg, 42%) as a yellow solid. MS ISP (m/e): 234.3 (100), 334 (24), 405.3 (69) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.61 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.38 (d, 1H), 7.20 (d, 1H), 7.02 (s, 1H), 3.80 (s, 3H), 2.55-2.80 (m, 4H), 2.14 (s, 3H), 2.04 (m, 2H), 1.60-1.80 (m, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][C@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), (1R,2S)-ethyl 2-aminocyclohexanecarboxylate hydrochloride (9.08 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=531.7 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.13 (t, J=7.1 Hz, 3H), 1.27 (d, J=6.8 Hz, 0.4H), 1.32-1.41 (m, 3H), 1.41-1.54 (m, 2H), 1.46 (d, J=7.1 Hz, 2.6H), 1.55-1.66 (m, 2H), 1.67-1.84 (m, 6H), 1.98-2.11 (m, 3H), 2.22-2.32 (m, 1H), 2.45-2.55 (m, 3H), 2.62-2.68 (m, 1H), 3.06-3.18 (m, 4H), 3.35-3.47 (m, 1H), 3.49-3.60 (m, 1H), 3.73-3.85 (m, 1H), 3.92-4.01 (m, 2H), 4.02-4.11 (m, 1H), 6.19 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.60-7.67 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12]C(=O)OC(C)(C)C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:20].O1CCOCC1>>[Cl-:20].[OH:1][CH2:2][CH:3]([NH3+:12])[C:4](=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)c1ccccc1
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]C(CO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 84.3 %

Procedure:
tert-butyl 3-hydroxy-1-oxo-1-phenylpropan-2-ylcarbamate (19) (270 mg, 1.0 mmol, 1.0 equiv) was added to a 25 mL RBF and a 4.0 N HCl-Dioxane solution (7.5 mL, 30.0 mmol, 30.0 equiv.) was added. The solution was stirred at rt. for 25 min, and 5 mL dioxane was evaporated with a steady stream of N2 (g). Next, Et2O (10 mL) was added to the reaction flask and a white precipitate formed. The soln was stirred for 10 min and filtered with a Buchner funnel. The precipitate was dried under vacuum to give 170 mg (86%) of 6 as a white solid. mp=160-162° C.; 1H NMR (500 MHz, DMSO) δ 8.94 (s, 3H, CH—NH3) 8.07 (d, J=7.0 Hz, 2H, Ph-H), 7.73 (t, J=7.0 Hz, 1H, Ph-H), 7.59 (t, J=7.5 Hz, 2H, Ph-H), 5.53 (br s, 1H, CH2—OH), 5.19 (s, 1H, +NH3—CH), 3.94 (d, J=11.5 Hz, 1H, CH—CH2), 3.85 (d, J=11.5 Hz, 1H, CH—CH2); 13C NMR (125 MHz, DMSO) δ 194.5, 134.3, 133.7, 129.1, 128.8, 60.6, 57.6; LRMS (ESI-MS, n/z): Mass calcd for C9H12NO2 [M]+, 166.20. Found 166. Anal. calcd for C9H12ClNO2: C, 53.61; H, 6.00; N, 6.95 Found: C, 53.26; H, 6.13; N, 6.96.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([CH:13]=[CH2:14])[C:9]([F:15])=[C:8]([F:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+](=[CH2:19])=[N-].C(OCC)C.CN(N=O)C(N)=O>C(OCC)C.C1(C)C(C)=CC=CC=1>[CH:13]1([C:10]2[C:11]([F:12])=[C:2]([F:1])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:8]([F:16])[C:9]=2[F:15])[CH2:19][CH2:14]1
Reactant: C=Cc1c(F)c(F)c(C(=O)OC)c(F)c1F
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COC(=O)c1c(F)c(F)c(C2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
In 10 ml of diethyl ether was dissolved 2.0 g of methyl 2,3,5,6-tetrafluoro-4-vinylbenzoate. To the resulting solution was added, with ice-cooling, a diazomethane-diethyl ether solution prepared from 3.0 g of N-methyl-N-nitrosourea. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 15 ml of xylene and the resulting solution was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2.1 g (yield: 99.1%) of methyl 4-cyclopropyl-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH2:8]([O:15][C:16]1[C:24]2[N:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:23]=2[C:22]2[CH:21]([CH2:30][OH:31])[CH2:20][N:19](S(C)(=O)=O)[C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO.C1COCC1>[CH2:8]([O:15][C:16]1[C:24]2[N:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:23]=2[C:22]2[C@H:21]([CH2:30][OH:31])[CH2:20][NH:19][C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cn(C)c2c(OCc3ccccc3)cc3c(c12)C(CO)CN3S(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cn(C)c2c(OCc3ccccc3)cc3c(c12)[C@H](CO)CN3
Reaction time: 5 h

Procedure:
To a suspension of 2b (3.3 g, 5.0 mmol) in a mixture of methanol (50 mL) and THF (30 mL) was added 5 mL of 1 M sodium methoxide in methanol. The reaction mixture was stirred for 5 hours, becoming a clear solution in approximately 30 min. Acetic acid (0.3 mL) was added to neutralize sodium methoxide, and the solution was evaporated to dryness. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography on silica gel, eluting with 5% acetone in CH2Cl2, afforded 1.6 g (85%) of (1S)-2a as a white solid. This product was shown by NMR and CHN analysis to be identical with the racemic material (2a). (1R)-2a was prepared analogously from 2c.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[N:20]=[N:21][NH:22][CH:23]=3)=[C:9]([OH:24])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[N:20]=[N:21][NH:22][CH:23]=3)=[C:9]([OH:24])[C:8]2=[S:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c(O)c(CCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 84.8 %

Procedure:
Reaction of 159e (0.18 g, 0.532 mmol) and P4S10 (0.118 g, 0.266 mmol) under neat conditions as described for synthesis of 162b gave compound 162e (0.080 g, 42%) as a olive green semi-solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.83 (d, J=7.5 Hz, 2H), 7.76 (s, 1H), 7.41 (t, J=7.5 Hz, 2H), 7.32 (m, 2H), 6.94 (m, 1H), 6.72 (m, 1H), 4.49 (m, 2H), 4.40 (t, J=6.9 Hz, 2H), 1.97 (m, 4H), 1.36 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 164.38, 162.90, 147.70, 130.54, 128.76, 128.03, 126.64, 125.61, 119.51, 118.75, 118.29, 59.74, 50.10, 29.91, 27.99, 25.82, 25.65. HRMS (ESI) calcd for C19H23N4OS [M+H]+ 355.158. found 355.1632.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.CO.O.[OH-].[Na+]>C1COCC1>[Br:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[N:15]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=3[CH2:9][CH2:10][O:11][C:12]=2[CH:19]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Yield: 60.8 %

Procedure:
A mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (3.32 g, 9.38 mmol), MeOH (75 mL) and water (50 mL) was treated with sodium hydroxide (562 mg, 14.06 mmol) at RT. After 90 minutes THF (20 mL) was added to aid dissolution. After 60 minutes the mixture was concentrated in vacuo, dissolved in water (200 mL) and carefully acidified to pH1 with 2N HCl. The resulting solid was collected by filtration, washed with water and dried under vacuum to afford 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.86 g, 61%). LCMS RT=4.91 min, no [M+H]+=326/328
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[NH:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[CH:8][CH:7]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C@:17]3([C@@H:16]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[F:42])[C@H:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:43])=[O:2])=[CH:7][CH:8]=4)=[O:14])[NH:19][C@H:18]3[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:32]2=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(OCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenoxy)-acetic acid methyl ester (45 mg, 0.071 mmol) in THF (3 mL) was added LiOH monohydrate (13 mg, 0.30 mmol) in water (2 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenoxy)-acetic acid as a white solid (36 mg, 80%). MS (ES+) m/z [(M+H)+]: 614
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8](F)=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:4]=1)[CH3:2].[C-:19]#[N:20].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CS(C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]#[N:20])=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(C2CCOCC2)c2nc(F)ccc12
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1nn(C2CCOCC2)c2nc(C#N)ccc12
Temperature: 150 °C
Yield: 74 %

Procedure:
A mixture of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine (2.92 g, 0.0117 mol), sodium cyanide (3.9 g, 0.079 mol), tetra-N-butylammonium bromide (7.6 g, 0.023 mol) and dimethyl sulfoxide (60 mL) was heated at 150° C. for 2 hours. After cooling, the product was extracted using ethyl acetate (300 mL). The extract was washed with water (5×50 mL) and brine (50 mL), and then concentrated to provide the crude product as a brown solid, which was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient over 15 minutes (flow rate 20 mL/min) to afford 2.22 g (73.9%) of 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carbonitrile as an off-white solid, which was used without further purification. LC/MS (EI) tR 3.57 (Method E), m/z 257.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:32])[NH:21][C:22]([CH3:31])=[CH:23][C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)CCl.CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:32])[NH:21][C:22]([CH3:31])=[CH:23][C:24]=2[C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Reactant: Cc1cc(-c2ccncc2)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1cc(-c2ccncc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.2 %

Procedure:
To a reaction vial were added 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (90 mg, 0.318 mmol), 3-(aminomethyl)-6-methyl-4,4′-bipyridin-2(1H)-one (103 mg, 0.477 mmol), 1-hydroxy-7-azabenzotriazole (64.9 mg, 0.477 mmol), EDC (91 mg, 0.477 mmol) and DMSO (10 mL) followed by N-methylmorpholine (0.140 mL, 1.272 mmol) in one portion. The reaction contents were stirred at RT for 12 hr, after which time an additional 20 mg each of amine, EDC, and HOAt were added. After stirring for an additional 2 h, the reaction mixture was poured onto ice water (10 mL), stirred for 20 min, allowed to stand for 10 min, and filtered. The collected solid was rinsed with water (10 mL), and then purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The product fractions were treated with NaHCO3 (sat aq), extracted with EtOAc, and evaporated from water to afford the final product as a white solid (69 mg, 43%). 1H NMR (400 MHz, DMSO-d6) ppm 11.95 (s, 1H), 8.63-8.65 (d, 2H), 8.60 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.61 (s, 1H), 7.42 (d, 2H), 6.00 (s, 1H), 5.02 (m, 2H), 4.15 (s, 2H), 2.23 (s, 3H), 1.45 (d, 6H); MS(ES) [M+H]+ 481.8.
Reaction SMILES: C(OC([N:8]([C:16]1[N:17]=[CH:18][CH:19]=[C:20]2[CH:24]=[C:23]([Sn](C)(C)C)[O:22][C:21]=12)C(OC(C)(C)C)=O)=O)(C)(C)C.Br[C:30]1[N:34]2[CH:35]=[CH:36][N:37]=[CH:38][C:33]2=[N:32][CH:31]=1.[F-].[Cs+]>O1CCOCC1>[N:32]1[CH:31]=[C:30]([C:23]2[O:22][C:21]3=[C:16]([NH2:8])[N:17]=[CH:18][CH:19]=[C:20]3[CH:24]=2)[N:34]2[CH:35]=[CH:36][N:37]=[CH:38][C:33]=12
Reactant: Brc1cnc2cnccn12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc([Sn](C)(C)C)oc12
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Nc1nccc2cc(-c3cnc4cnccn34)oc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
A mixture of di-tert-butyl[2-(trimethylstannanyl)furo[2,3-c]pyridin-7-yl]imidodicarbonate (0.0994 g, 0.200 mmol) in 1,4-dioxane (1.5 mL) was degassed with nitrogen for 10 min. To this mixture was added 3-bromoimidazo[1,2-a]pyrazine (0.033 g, 0.17 mmol), Pd(FPh3)4 (0.0192 g, 0.0167 mmol) and cesium fluoride (0.0850 g, 0.560 mmol). The temperature was raised to 100° C. and the mixture was heated for 16 h. Following removal of solvent, the residue was purified by ISCO chromatography (0 to 10% methanol:DCM). The resultant material was dissolved in dichloromethane (2 mL) and cooled to 0° C. To this mixture was slowly added TFA (2 mL). The ice bath was removed and the mixture was stirred for 2 h and then concentrated to a light brown residue. The residue was dissolved in DCM (30 mL) and saturated aqueous sodium bicarbonate (5 mL) was added and then the mixture was concentrated. Purification by ISCO chromatography (0 to 20% methanol:DCM) afforded 0.021 g (49%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ=9.19 (dd, J=1.4, 4.7 Hz, 1 H), 9.17 (d, J=1.5 Hz, 1 H), 8.46 (s, 1 H), 7.76 (dd, J=4.3, 5.6 Hz, 2 H), 7.43 (s, 1 H), 7.37 (s, 1 H); MS (ESI): 252.17 [M+H]+.