Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:22](=[O:24])[CH3:23])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid benzyl ester (600 mg, 2.39 mmol) in THF (10 mL) at 0° C. under nitrogen was added NaH (60% in mineral oil, 191 mg, 4.78 mmol). The mixture was stirred for 20 min at 0° C., acetyl chloride (339 μl, 4.78 mmol) was added and the resulting suspension was stirred at RT for 48 h. The solvent was concentrated and the residue poured in water and extracted twice with CH2Cl2. The Combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 75:25) to give the desired product as a white solid. TLC, Rf (c-hexane/EtOAc 3:1)=0.38; MS (LC-MS): 294.1 [M+H]+, 316.0 [M+Na]+; tR (HPLC conditions a): 4.69 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])([CH3:5])[CH3:4].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[C:17]([C:16]1[C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=[CH:20][C:19]=1[O:1][CH2:2][C:3]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])([CH3:5])[CH3:4])#[N:18]
Reactant: CCCC(=O)NC(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCCC(=O)NC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 72 %

Procedure:
Prepared as in Example 197c from N-(1-hydroxy-2-methylpropan-2-yl)butyramide (Example 208d) and 2,6-dinitrobenzonitrile in 72% yield. MS 306 (MH+).
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[C:11]1([S:17][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[C:11]1([S:17][C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:10])[F:1])=[CH:20][CH:19]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCCC=C(F)F
Reactant: Nc1ccc(Sc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCC=C(F)F)Nc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling at 10°, 8.5 g of 6,6-difluorohex-5-enoic acid chloride are added to 10.0 g of 4-phenylthioaniline, 6.5 g of triethylamine and 100 mg of 4-N-pyrrolidinopyridine in 250 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and then concentrated by evaporation in vacuo. The residue is taken up in toluene, the toluene phase is washed with water, dried over sodium sulfate and 90-95% of the amount of toluene is evaporated off in vacuo. While the mixture is still warm, a small amount of hexane is added, which causes the product to crystallise out. The mixture is cooled and filtered, and the filter residue is washed with hexane, yielding the title compound having a melting point of 80°-81° (compound no. 2-1).
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:27][N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CCCCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.5 %

Procedure:
Solid Teoc-OSu (390 mg, 1.5 mmol) was added to a vigorously stirred 2-phase mixture of (2S)-2-(tert-butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane (312.8 mg, 1.0 mmol), Na2CO3 (525 mg, 5.0 mmol), H2O (5.0 mL), and CH2Cl2 (25.0 mL). The mixture was stirred for 90 min at rt and the reaction was taken up in CH2Cl2 (50 mL), washed with brine (3×10 mL), dried over Na2SO4, decanted, and stripped to give a clear oil. This oil was separated on a 4 g SiO2 column to give crude (2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (486.5 mg, 106%) as a clear oil (quant). MS ESI+ve m/z 479 (M+Na). The crude product was used without further purification.
Reaction SMILES: O[CH2:2][N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[C:4]1=[O:5].S(Cl)([Cl:16])=O>>[Cl:16][CH2:2][N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[C:4]1=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C1C(=O)N(CO)c2ccccc21
Product: O=C1C(=O)N(CCl)c2ccccc21

Procedure:
N-Hydroxymethylisatin (10 g, 0.056 mol) was added to thionyl chloride (100 ml) and the mixture was heated under reflux for 2 hours. N-Chloromethylisatin (about 11 g) was obtained by distilling the remaining thionyl chloride under reduced pressure. The melting point was 121° to 123° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C12BC(CCC1)CCC2.[OH-:34].[Na+].OO>O1CCCC1.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:34])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 71.6 %

Procedure:
To 1-(4-(trifluoromethoxy)phenyl)-3-(4-vinylphenyl)-1H-1,2,4-triazole (C43) (2.0 g, 6.0 mmol) in tetrahydrofuran (50 mL) was added 9-borabicyclo(3.3.1)nonane (24 mL, 12.1 mmol), and the reaction was stirred at room temperature for 4.5 hours. Sodium hydroxide (3 N, 4.0 mL, 12.0 mmol) was added, followed by hydrogen peroxide (30% wt, 1.5 mL, 15.1 mmol). The light green solution was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a light green oil. The crude compound was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (1.5 g, 69%): mp 85-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.06 (d, J=9.0 Hz, 2H), 8.01 (d, J=8.1 Hz, 2H), 7.61 (dd, J=9.2, 1.0 Hz, 2H), 7.41-7.30 (m, 2H), 4.69 (t, J=5.2 Hz, 1H), 3.65 (td, J=7.0, 5.1 Hz, 2H), 2.79 (t, J=6.9 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 162.18, 147.08, 143.70, 141.45, 135.72, 129.39, 128.23, 127.93, 125.96, 122.57, 121.10, 61.90, 61.90; 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 349 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Br:7].[Br-].[C:15]1([PH+:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:7].[C:28]1([P+:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][C:2]([F:13])([F:12])[F:1])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: [Br-]
Solvent: CC#N
Product: FC(F)(F)Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
5 g (26 mmol) of 2-trifluoromethoxybenzyl bromide and 8.5 g (24.7 mmol) of triphenylphosphonium bromide are stirred under reflux in 100 ml of acetonitrile for 3 h. After cooling, the resulting precipitate is filtered off with suction and dried. 13.5 g (26 mmol, 100% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:13]=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[CH3:26])[C:20]([OH:22])=O)[CH:16]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:27]([C:31]1[CH:32]=[C:33]([NH2:38])[C:34]([CH3:37])=[N:35][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[C:33]([NH:38][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:17]([N:15]3[CH:16]=[C:12]([C:9]4[CH:10]=[N:11][C:6]([NH:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)=[CH:7][CH:8]=4)[N:13]=[N:14]3)[CH:18]=2)[C:34]([CH3:37])=[N:35][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(NCC3CC3)nc2)nn1
Reactant: Cc1ncc(C(C)(C)C)cc1N
Product: Cc1ccc(C(=O)Nc2cc(C(C)(C)C)cnc2C)cc1-n1cc(-c2ccc(NCC3CC3)nc2)nn1

Procedure:
Example 2 was prepared by coupling 3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzoic acid with 5-tert-butyl-2-methyl-pyridin-3-ylamine (See U.S. provisional application 60/567,693) in the same manner as Example 1. ESI MS m/z 496 [C29H33N7O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([C:21]#[N:22])[CH:3]=1.[H][H]>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[C:4]([C:21]#[N:22])[CH:3]=1
Reactant: N#Cc1cc(Cl)ccc1-c1ccc(C(O)/C=C/C(=O)O)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)ccc1-c1ccc(C(O)CCC(=O)O)cc1

Procedure:
9.90 gm (0.0316 mol) of 4-(4'-chloro-2'-cyano-4-biphenylyl)-4-hydroxy-crotonic acid in 500 ml of dry ethyl acetate were hydrogenated in the presence of 2.50 gm of Raney nickel, at a hydrogen pressure of 5 atmospheres and at room temperature until the end of hydrogen absorption. After filtering, the filtrate was washed twice with 100 ml of 1% hydrochloric acid each and then with water, dried over sodium sulfate and evaporated in vacuo. The oily, yellowish residue was dissolved in ethyl acetate and converted into the cyclohexylamine salt by addition of the equimolar quantity of cyclohexylamine. Yield: 6.15 gm; m.p. 168°-169° C. (from acetone/ethyl acetate 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:20][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(N1CCc2c(F)cc(Cl)c(O)c2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(N1CCc2c(F)cc(Cl)c(OCc3ccc(F)cc3)c2CC1)C(F)(F)F
Reaction time: 14 h

Procedure:
Dissolve 7-chloro-9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.25 g, 0.8 mmol) in DMF (8 mL), add potassium carbonate (0.56 g, 4.0 mmol) and 4-fluorobenzyl bromide (0.46 mL, 2.4 mmol). After 14 h at 90° C., dilute with ether and wash with brine. Dry the organic layer over Na2SO4 and evaporate onto silica gel. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:0) to obtain 7-chloro-9-fluoro-6-(4-fluorobenzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCCCCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCCCCCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as in Example 81, 162 mg of the title compound was prepared from 218 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 0.095 ml of 1-iodohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:51][C:52]1[CH:61]=[CH:60][CH:59]=[C:58]2[C:53]=1[CH:54]=[CH:55][N:56]([C@@H:63]([CH3:67])[C:64]([NH2:66])=[O:65])[C:57]2=[O:62]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:51][C:52]2[CH:61]=[CH:60][CH:59]=[C:58]3[C:53]=2[CH:54]=[CH:55][N:56]([C@@H:63]([CH3:67])[C:64]([NH2:66])=[O:65])[C:57]3=[O:62])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3,4-dichlorophenyl acetic acid (0.12 g, 0.00056 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0009 mol) and N,N-diisopropylethylamine (0.2 mL, 0.0009 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added (S)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (0.10 g, 0.00043 mol). The reaction was stirred for 16 h at room temperature. The reaction was quenched with water, extracted with dichloromethane, washed with 2N HCl, saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (12 g, 0-10% MeOH/DCM) to yield the product as a white solid.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 11.02 g of isoamyl nitrite and 45 ml of acetonitrile was added dropwise to a mixture of 15.16 g of methyl [2-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, 6.21 g of copper(I) chloride, 12.65 g of copper(II) chloride, and 250 ml of acetonitrile at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 13 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17].C(=O)([O-])O.[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:16][CH3:17])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(Br)cn1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 5-bromopyridine-2-carboxylic acid (35.0 g, 173 mmol), sulfuric acid (12.0 mL) and ethanol (300 mL) was stirred at 75° C. for 2 hr. After cooling to 0° C., the mixture was neutralized with sodium hydrogen carbonate and diluted with water (150 mL). Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (300 mL). The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was collected by filtration, washed with hexane, and dried to give the title compound (34.5 g, 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C1COCC1.[H][H]>[OH-].[OH-].[Pd+2].CO>[Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
32.6 grams (0.118 mol) of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid was added to a one liter round bottom flask along with 250 mL of a 1:1 (v/v) mixture of THF and methanol. 3.3 grams of 20% palladium hydroxide on carbon was then added and the flask was fitted with a septa and balloon of hydrogen. The mixture was stirred overnight at room temperature. In the morning, the crude product was filtered through a pad of celite and the pad was washed with THF. The product was evaporated to dryness and triturated with cold diethyl ether to give 32.1 grams of a tan solid (98% yield, 85% purity, UV detection λ=220 nm) that was used without further purification. MS m/z 278.00 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=[O:14])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].CC(=CC)C.Cl([O-])=[O:40].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:16]([NH:15][C@H:11]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=4)[CH2:12][C:13]([OH:40])=[O:14])=[O:17])[C:19]=3[CH:26]=[N:25]2)=[CH:32][CH:31]=1
Reactant: [O-][Cl+][O-]
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CS(=O)(=O)c1cc([C@H](CC(=O)O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 8 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (0.10 g, 0.21 mmol) and 2-methyl-2-butene (147 μL, 1.39 mmol) in t-butanol (1 mL) was added a solution of 80% sodium chlorite (31 mg, 0.28 mmol) and sodium dihydrogen phosphate monohydrate (38 mg, 0.28 mmol) in water (400 μL) (addition was exothermic). The mixture stirred overnight and was then concentrated in vacuo, acidified with 1 N aqueous HCl (pH=2), diluted with brine (25 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propionic acid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9]O.CCN(S(F)(F)[F:17])CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][F:17]
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cc(I)ccc1F
Solvent: ClCCl
Product: FCc1cc(I)ccc1F
Temperature: 25 °C

Procedure:
To a stirred solution of (2-Fluoro-5-iodo-phenyl)-methanol (1.0 g, 3.97 mmol) in dry methylene chloride (10 mL) at −78° C. and under a nitrogen atmosphere was added DAST (0.63 mL, 4.76 mmol). The cooling bath was removed and the mixture was warmed to room temperature for 1 h, and then quenched with sat sodium bicarbonate (4 mL). The mixture was partitioned between methylene chloride and H2O, and the aqueous layer was extracted with methylene chloride (2×10 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated in vacuo to a clear oil (0.999 g, 99%) and used directly in the next step.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[N:5]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH:35]3[CH2:37][CH2:36]3)=[CH:27][CH:26]=2)[C:6]([S:9][CH2:10][C:11](NC2C=CC(S(=O)(=O)N)=CC=2Cl)=[O:12])=[N:7][N:8]=1.C>C(O)C>[Br:3][C:4]1[N:5]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH:35]3[CH2:37][CH2:36]3)=[CH:27][CH:26]=2)[C:6]([S:9][CH2:10][C:11]([OH:1])=[O:12])=[N:7][N:8]=1
Reactant: [OH-]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CSc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)c(Cl)c1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydroxide solution (2M aqueous, 33.7 mL, 67 mmol, 2 eq) was added to a suspension of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N-(2-chloro-4-sulfamoylphenyl)acetamide (prepared by previously published procedures; 20 g, 34 mmol) in ethanol (200 mL) and the mixture heated at reflux for 4 hours. Charcoal (10 g) was added, the mixture stirred at room temperature for 12 hours and the charcoal removed by filtration. The charcoal was washed several times with ethanol and the filtrate then concentrated. Water (200 mL) was added and then concentrated to approx. one third volume, to remove all ethanol. Water (200 mL) and ethyl acetate (250 mL) were added, the mixture stirred vigorously for 15 mins and the organic layer removed. The aqueous layer was cooled to 0° C. and acidified by treatment with HCl (IN) resulting in the formation of a cloudy oily precipitate. The mixture was extracted with ethyl acetate (3×) and the combined organic extracts dried over sodium sulfate and concentrated to give 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off white solid (11.2 g, 82%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][CH2:17][C:18]1[C:19]([NH:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:20]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]2=[N:22][C:23]=1[CH2:24][CH3:25])=[O:15])=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=3[NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])[C:19]([NH:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CNCCO
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCN(C)CCO
Temperature: 60 °C

Procedure:
A solution of 2-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (68 mg, 0.11 mmol, e.g. which can be as prepared in Intermediate 46) in N,N-dimethylformamide (5 ml) was treated with 2-(methylamino)ethanol (0.0175 ml, 0.22 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.038 ml, 0.22 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (5 mg). LCMS showed MH+=622; TRET=2.15 min.