Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[N:6][S:5][N:4]=1.[C-:15]#[N:16].[Na+].O>CN(C)C=O>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]([CH2:2][C:15]#[N:16])=[N:4][S:5][N:6]=1
Reactant: Clc1ccccc1-c1nsnc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1nsnc1-c1ccccc1Cl
Yield: 63.7 %

Procedure:
In N,N-dimethylformamide, 290 mg of 3-bromomethyl-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 49 mg of sodium cyanide were stirred at 90° C. for 3 hours. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole. The obtained 150 mg of 3-(2-chlorophenyl)-4-cyanomethyl-1,2,5-thiadiazole, 6 mL of 5% sodium hydroxide solution, and 2 mL of ethanol were mixed and refluxed by heating for one hour. After spontaneous cooling, the reaction mixture was poured into dilute hydrochloric acid, and was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of [3-(2-chlorophenyl)-1,2,5-thiadiazole-4-yl]acetic acid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:35])[CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Cl.[NH2:37][C:38](N)=[O:39].C([O-])(O)=O.[Na+]>O.CCO>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH:3]([OH:35])[CH2:2][NH:1][C:38]([NH2:37])=[O:39])([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[O:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1
Reactant: NC(N)=O
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(O)CN)(c2ccc(F)cc2)OC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(O)CNC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C

Procedure:
To a solution of (6S)-6-(3-amino-2-hydroxypropyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (300 mg, 0.62 mmol) in H2O (10 mL) was added HCl (12 N, 0.05 mL), urea (372 mg, 6.2 mmol) and EtOH (2 mL). Then the mixture was heated to reflux overnight. The reaction mixture was cooled to rt and adjusted pH to 9˜10 by saturated NaHCO3 solution. The mixture was concentrated and extracted by CH2Cl2. The combined organic layer was dried and concentrated to give the residue, which was purified by preparative HPLC followed by chiral preparative HPLC to give two isomers.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].CN(C)C=O.[CH3:24][NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:30][CH2:31][CH:27]([CH2:26][NH:25][CH3:24])[CH2:28]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CNCC1CCNC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC)C3)cc21
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture of 1.00 g (3.95 mmole) 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml N,N-dimethylformamide, 75 ml acetonitrile, and 1.35 g (11.85 mmole) of N-methyl-3-pyrrolidinemethanamine were refluxed overnight The reaction was cooled to room temperature and filtered. The precipitate was washed with water, ethanol/ether (1:3), and finally with ether until dry to give 1.17 g of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid, mp 247°-250° C.
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]2=[N:6][CH:5]=1.Cl[CH2:19][C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH3:14][C:2]([N+:15]([O-:17])=[O:16])([CH3:1])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:19][C:20]([NH2:22])=[O:21])=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: NC(=O)CCl
Reactant: CC(C)(Cc1cnc2cc(O)ccn12)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(Cc1cnc2cc(OCC(N)=O)ccn12)[N+](=O)[O-]
Yield: 34.3 %

Procedure:
3-(2-Methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-ol (1.5 g, 6.38 mmol), chloroacetamide (1.19 g, 12.73 mmol), potassium carbonate (6.4 mmol) and a small amount of potassium iodide in 2-butanone (30 ml) is heated at reflux overnight. The solids are removed by filtration and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel with dichloromethane/methanol 3:1 to 1:1 to give 640 mg of 2-[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-yloxy]-acetamide (34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:26])[C:11](=[O:27])[CH2:10][N:9]=1.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([O:25][CH2:24][CH2:23][NH:22][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:26])[C:11](=[O:27])[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)=[O:21])(=[O:30])[CH3:29]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C

Procedure:
11.1 g (0.03 M) of 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea are stirred at room temperature for 18 hours in 150 ml of acetonitrile with 3.9 ml of acetyl chloride and 9 g of powdered potassium carbonate. The mixture is concentrated on a rotary evaporator and the residue is purified on a 500 g silica gel column using methylene chloride/ethanol as the eluting agent. After crystallisation from ethyl acetate, there is obtained 2-[3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate which melts at 196°-198° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][C:19]=2[O:30][CH3:31])[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:11]2[CH:32]=[CH:33][CH:34]=[C:9]([Cl:8])[C:10]=2[F:35])[CH2:25]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (89 μl) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (469 mg; prepared as described in Example 45) and diisopropylethylamine (700 μl) in methylene chloride (15 ml) that was cooled to 0° C. The mixture was stirred at room temperature for 2 hours to give 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH:30]1([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:39][S:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:38])=[O:37])=[O:27])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: NS(=O)(=O)C1CCCCC1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(=O)(=O)C2CCCCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and cyclohexanesulfonamide (Helv. Chim. Acta 1975, 58, 2321): 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.14 (1H, d, J=2.6 Hz), 8.15–8.08 (1H, m), 7.81 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.3 Hz), 7.22–7.10 (4H, m), 5.42–5.30 (1H, m), 3.80–3.65 (1H, m), 2.26–2.16 (2H, m), 1.98–1.85 (2H, m), 1.78–1.50 (4H, m), 1.60 (3H, d, J=7.0 Hz), 1.43–1.15 (2H, m); MS (ESI) m/z 560 (M+H)+, 558 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.C[N:20](C=O)C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:20])=[O:12]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of indole-2-carboxylic acid (1 g, 6.21 mmol) in MC (30 ml), oxalyl chloride (1.64 ml, 0.18.62 mmol) and a catalytic amount of DMF were added and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was diluted with MC (20 ml), to which a solution of ammonium hydroxide in water (7 ml) was dropwise added with cooling in an ice bath. After stirring for 1 hr, the precipitated product was collected by suction filtration, triturated in hexane and dried to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[O:8][C:7]=1[CH3:14])=[O:5])[CH3:2].S(N)(=O)(=O)[OH:16].Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:11][C:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[O:8][C:9]=1[C:12]([OH:16])=[O:13]
Reactant: CCOC(=O)c1c(C)oc(C=O)c1C
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C)oc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4-Dimethyl-5-formylfuran-3-carboxylic acid ethyl ester (1.78 g, 9.1 mmol) reported in the references was dissolved in a mixture of acetic acid (32 ml) and water (8 ml). Amidosulfuric acid (1.19 g, 12.2 mmol) was added to the solution, and cooled to 0° C. in an ice bath. Sodium chlorite was added and stirred for 2 hours, and after addition of water to reaction mixture, precipitate was collected by filtration, thereby giving 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (1.01 g, 52%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CN(C)C=O.[I-].C[N+](C)(C)[CH2:17][C:18]([C:20]1[C:29]2[CH:28]=[N:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=2[CH2:23][CH2:22][CH:21]=1)=[CH2:19]>C(N(CC)CC)C>[CH3:31][O:30][C:26]1[N:27]=[CH:28][C:29]2[C:20]([C:18]([CH2:17][C:2]3([CH3:1])[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[CH2:19])=[CH:21][CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: CC1C(=O)CCC1=O
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ncc21
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(CC1(C)C(=O)CCC1=O)C1=CCCc2cc(OC)ncc21
Temperature: 25 °C

Procedure:
A solution containing 0.75 parts of 2-methylcyclopentane-1,3-dione in 19 parts of dimethylformamide is treated sequentially with 1.0 part by volume of triethylamine and 1.9 parts of N,N,N-trimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)ammonium iodide. The resulting homogeneous solution is heated at about 135° for 4 3/4 hours. It is allowed to cool to room temperature and solvent is removed under reduced pressure. The remaining material is diluted with water-ether and enough 5% sodium hydroxide solution is added to bring the pH to 10. The aqueous and organic layers are separated and the aqueous layer is extracted with ether. The extracts are washed sequentially with 5% sodium hydroxide solution, 2.5% aqueous formic acid and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. Upon solvent removal, an oil remains which is taken into ether. Then n-hexane is added until the solution becomes turbid. Charcoal is added and the mixture is filtered. Solvent is removed under reduced pressure to yield an oil which crystallizes upon standing. Recrystallization from acetone-water gives pure 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoquinoline, which is identical to the product obtained in Example 9 A.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].O>O1CCCC1>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][N:19]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12]
Reactant: O=C(CCCCCl)c1ccc2c(c1)CCNCC2
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)N1CCc2ccc(C(=O)CCCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl isocyanate (781 μl) was added to a solution of 5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.3 g) obtained in Reference Example 121 in tetrahydrofuran (30 ml). After stirring at room temperature for 60 minutes, water (50 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a colorless solid (2.2 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:13])=[O:12])=[O:4].O.O.[OH-].[Li+].Cl>CO>[CH3:28][O:27][C:25]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[NH:14][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2])(=[O:12])=[O:13])=[O:26]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)O)ccc2ccccc12
Temperature: 60 °C

Procedure:
A solution of Example 149A (0.60 g, 1.50 mmol) in methanol (16 mL) and distilled water (1.8 mL) was treated with lithium hydroxide monohydrate (0.19 g, 4.50 mmol), heated to 60° C. for four days, cooled to room temperature treated with 1N HCl, and extracted with ethyl acetate (2×). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(−)) m/e 384 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 14.25 (br s, 1H), 9.38 (br s, 1H), 8.06 (d, 1H), 7.94 (dd, 1H), 7.80 (m, 3H), 7.72 (dt, 1H), 7.66 (d, 1H), 7.62 (dd, 1H), 7.54 (dt, 2H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[C:8]=2[OH:24])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:7]2[C:8]([OH:24])=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)=[O:35])=[CH:25][CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cc2ccc(F)cc2)c(O)c1-c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(O)c1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Synthesis of 3-(4-Fluoro-benzyl)-6-methoxy-3′-nitro-biphenyl-2-ol (P-099) In an 8 mL vial equipped with a stir bar was placed I-246 (60 mg, 0.163 mmol) and triethylsilane (350 μL). The mixture was cooled in an ice-water bath and then TFA (350 μL) was added. The reaction mixture was warmed to room temperature and reacted for 17 hours. After this time period, additional triethylsilane (1.1 mL) and TFA (1.1 mL) was introduced and the reaction mixture was heated to 60° C. in an oil bath for 24 hours. The reaction mixture was concentrated by a stream of N2, quenched with water (20 mL) and extracted with dichloromethane (2×30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography utilizing 15% EtOAc/hexanes as the eluent to produce 18.9 mg of P-099 as a viscous, tan oil in 33% yield. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.94 (s, 2H), 4.73 (s, 1H), 6.55 (d, J=8 Hz, 1H), 6.96-7.00 (m, 2H), 7.01 (d, J=8 Hz, 1H), 7.19-7.22 (m, 2H), 7.63 (t, J=7 Hz, 1H), 7.69 (dt, J=8, 2 Hz, 1H), 8.22-8.26 (m, 2H) ppm. MS (APCI−): 352.1 (M−1); LC-MS: 98%.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[Br:35][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[CH:8]=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)cc1=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.) solution of 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (5.76 g, 15.5 mmol) in DCM (35 mL) was added NBS (2.48 g, 13.9 mmol). Allowed reaction to warm to ambient temperature. After 5 h, cooled (0° C.) reaction mixture, filtered solid, washed with cold DCM and cold hexane, and dried in vacuo. Obtained product as orange solid (5.57 g, 80%). Used without further purification. 1H NMR (CD3OD/400 MHz) δ8.29 (s, 1H), 8.05 (m, 1H), 7.91 (s, 1H), 7.60 (q, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 6.99 (m, 2H), 5.57 (s, 2H), 2.17 (s, 3H). ESHRMS m/z 451.0095 (M+H calculated for C19H14BrF2N2O4 requires 451.0100).
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]2[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=2[C:25]#[N:26])=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[H-].[Na+].I[CH3:36]>CN(C=O)C>[Cl:1][C:2]1[C:18]([C:19]2[CH:20]=[N:21][C:22]([C:27]([F:29])([F:28])[F:30])=[CH:23][C:24]=2[C:25]#[N:26])=[CH:17][C:5]([C:6]([N:8]([C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])[CH3:36])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: CI
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Nc1c(C)cccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
To 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide (55.0 mg, 0.12 mmol) in dry DMF (0.5 mL) was added NaH (9.6 mg, 0.32 mmol) and iodomethane (0.15 mL, 0.24 mmol). The mixture was stirred at rt overnight, quenched with 0.5 mL of MeOH and 2 drops of trifluoroacetic acid, and purified via reverse phase preparative LCMS to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-N-methyl-benzamide 39-1 (8.3 mg). MS [M+H]+ 471.1; tR=6.25 min (method 3)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:25])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[CH3:37]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Reactant: Cc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.110 g, 2.75 mmol), 1-(3-bromo-4-methylphenyl)methanamine (0.600 g, 3.00 mmol), HATU (1.331 g, 3.5 mmol) and triethylamine (0.976 ml, 7.0 mmol) in dichloromethane (35 mL) was stirred at room temperature under N2. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4, and then evaporated to dryness which gave, initially, a glassy gum, but then appeared to very slowly crystallize. The residue was taken up in a small amount of MeOH and sonicated whereupon a crystalline white solid formed and was collected and dried to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.16 g, 72%). LC-MS m/z 585.4 (M+H)+, 0.87 min (ret time).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])=[N:6][CH:7]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)=[CH:7][N:6]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cn4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(Cl)cc5)cn4)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 36 h
Yield: 56.4 %

Procedure:
Ethyl 7-(4-(5-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.094 mmol), 4-chlorophenylboronic acid (15 mg, 0.094 mmol), Na2CO3 (25 mg, 0.24 mmol) and Pd(PPh3)4 (11 mg, 0.0094 mmol) were placed in a 1 mL vial and diluted with toluene (800 μL) and water (80 μL). The vial was purged with argon, sealed and heated to 100° C. After stirring for 36 hours, the reaction was loaded onto silica gel eluting with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield the desired compound (30 mg, 0.053 mmol, 57% yield).