Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:26]([CH:28]1[CH2:31][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44](Br)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:29]1)#[N:27]>CN(C=O)C.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.[Cu]I>[C:26]([CH:28]1[CH2:29][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH2:11][CH3:12])[N:7]=4)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:31]1)#[N:27]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CC)c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 80 °C
Yield: 102.8 %

Procedure:
To a solution of 6-chloro-1-ethyl-3-tributylstannyl-1H-indazole (125 mg, 0.27 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) in DMF (1.5 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 0.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to isolate 156 mg of 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a viscous colorless oil.
Reaction SMILES: [Mg].[CH:2](=O)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][C:13]1[S:17][S:16][C:15](=[S:18])[CH:14]=1>CO>[C:5]1([CH:4]=[CH:3][CH:2]=[CH:12][C:13]2[S:17][S:16][C:15](=[S:18])[CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CC=Cc1ccccc1
Reactant: Cc1cc(=S)ss1
Agent: [Mg]
Solvent: CO
Product: S=c1cc(C=CC=Cc2ccccc2)ss1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 40 ml of methanol, 600 mg (24 milligrams atom) of magnesium metal was added, and the mixture was heated to reflux for 1 hour to dissolve the magnesium metal. While cooling the mixture in ice water, 1.4 g (10 milli moles) of cinnamaldehyde, and then 1.56 g (10 milli moles) of 5-methyl-1,2-dithiol-3-thione were added to the mixture and the mixture was stirred for 1 hour at the same temperature. Separated crystals were recovered by filtration, and were added to 300 ml of ethyl acetate. Insolubles were removed by filtration, and the mother liquor was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from benzene-ethanol to obtain dark red crystals of
Reaction SMILES: C(N(CC)[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.[F:22][C:23]([F:27])([F:26])[C:24]#[N:25]>C1COCC1>[CH3:12][O:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:4]([OH:14])=[N:25][C:24]([C:23]([F:27])([F:26])[F:22])=[CH:13]2
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: N#CC(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1 g, 4.52 mmol) in THF (40 mL) was added tert-butyllithium (3.99 mL, 6.78 mmol) dropwise at −78° C. After stirring for 0.5 h, 2,2,2-trifluoroacetonitrile (0.472 g, 4.97 mmol) was bubbled through the solution via syringe for 1 minute, then warmed to rt, and stirred for 16 h. The reaction mixture was quenched with water (1 mL) and partially evaporated to half to one third of original volume, neutralized with 1 N HCl. The solution was separated with EtOAc. The organics were collected, washed with brine, dried over MgSO4, filtered and evaporated to give crude material as a dark yellow solid. The crude material was purified via silica gel chromatography (90 g column, 10-50% EtOAc:Hex) to give the product 6-methoxy-3-(trifluoromethyl)isoquinolin-1-ol (271 mg, 1.114 mmol, 24.66% yield) as a light yellow solid. MS: MS m/z 244.19(M++1).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:2].[Br:28]Br.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:28][CH2:2][C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:3]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(=O)CBr)CCN(C)C2=O

Procedure:
A solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.50 g, 1.35 mmol; Example 7, step 7), bromine (0.24 g, 1.49 mmol), 33% hydrobromide in glacial acetic acid (10 drops) in chloroform (15 mL) was stirred at room temperature for 6 hours. The mixture was treated with aqueous sodium bicarbonate and diluted with chloroform. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 20 to 80% ethyl acetate in hexane to afford the title compound. ES MS M+1=407, 409
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:17]([OH:19])=O)[CH:6]=1.[O:20]=[C:21]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[NH:37][O:38][C:39](=[O:41])[N:40]=3)[CH:34]=2)[O:29][C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22]1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:17]([N:26]2[CH2:27][CH2:28][C:23]3([CH2:22][C:21](=[O:20])[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)[CH:34]=4)[O:29]3)[CH2:24][CH2:25]2)=[O:19])[CH:6]=1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nc(=O)o[nH]3)cc21
Reactant: COc1cccc2c(OCCO)cc(C(=O)O)cc12
Product: COc1cccc2c(OCCO)cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5noc(=O)[nH]5)ccc3O4)cc12

Procedure:
The compound was prepared according to the procedure described in the Example 1, using 4-(2-hydroxyethoxy)-8-methoxy-2-naphthoic acid instead of 4,8-dimethoxyquinoline-2-carboxylic acid, and 3-[4-oxospiro(chroman-2,4′-piperidin)-6-yl]-5-oxo-1,2,4-oxadiazole instead of 4-oxospiro(chroman-2,4′-piperidin)-6-yl acetamide. 1H-NMR (400 MHz, DMSO-d6) δ; 8.24 (1H, d, J=4.0 Hz), 8.04 (1H, dd, J=4.0, 8.0 Hz), 7.86 (1H, d, J=8.0 Hz), 7.75 (1H, s), 7.51 (1H, t, J=8.0 Hz), 7.34 (1H, d, J=8 Hz), 7.09 (1H, d, J=8 Hz), 7.00 (1H, s), 4.40-4.22 (1H, m), 4.20 (2H, t, J=4.0 Hz), 4.01 (3H, s), 3.92-3.89 (2H, m), 3.75-3.30 (3H; m), 3.03 (2H, s), 2.12-1.75 (4H, m). MS [M+H]+=546.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[O:31]=[C:28]([NH:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1)[CH2:29][CH3:30]
Reactant: Nc1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
To a solution of trans-N-(7-amino-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (50 mg, 0.13 mmol) in CH2Cl2 (2 mL) was added propionyl chloride (11 μl, 0.13 mmol) and triethylamine (20 μl, 0.14 mmol). The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 (aq) and extracted with CH2Cl2. The organic layer was dried and evaporated. The crude product was purified on silica and by HPLC to afford the title compound (27 mg, 48%). Data (m/z)=434 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]=O>CO>[C:5]1([C@H:2]2[CH2:3][O:4][CH2:11][NH:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: C=O
Solvent: CO
Product: c1ccc([C@H]2COCN2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (1.5 g, 10.93 mmol) in methanol (36.4 mL) was added formaldehyde (1.065 g, 13.12 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to dryness. The crude material was purified by flash chromatography (0-50% EtOAc/heptanes) to give (S)-4-phenyloxazolidine in 40% yield. LCMS (m/z): 150.1 (MH+), 0.31 min.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8](Cl)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:23][CH2:24]2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(Cl)c2cc(OC)ccc12
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: CCCCc1nnc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 4-butyl-1-chloro-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([Br:33])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1F

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz in carbontetrachloride. The title compound, ESI MS (m/z): 549 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([O:15]C)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.9 %

Procedure:
10-bromo-2-methoxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (10.2 g) obtained in Example 1 was suspended in anhydrous methylene chloride (1000 ml), and boron tribromide (25 g) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 12 hours, and poured into ice water (500 ml). To this mixture was added saturated aqueous solution of sodium carbonate until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed in a mixture of methylene chloride and methanol to obtain the title compound (6.4 g, 65%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C@@H:10]1[CH2:14][O:13][C@@H:12]2[C@H:15]([O:18][C:19]3[N:20](COCC[Si](C)(C)C)[C:21]4[C:22]([N:40]=3)=[N:23][C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=3)=[C:25]([Cl:27])[CH:26]=4)[CH2:16][O:17][C@H:11]12>C(Cl)Cl>[CH3:8][O:9][C@@H:10]1[CH2:14][O:13][C@@H:12]2[C@H:15]([O:18][C:19]3[NH:20][C:21]4[C:22]([N:40]=3)=[N:23][C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=3)=[C:25]([Cl:27])[CH:26]=4)[CH2:16][O:17][C@H:11]12
Reactant: CO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TFA (0.7 ml, 9.09 mmol) was added to a stirred solution of 2-[[2-[[(3R,3aR,6R,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-5-(4-phenylphenyl)-imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane in DCM (0.7 ml). The reaction mixture was stirred at room temperature. After 1.5 hours, the reaction mixture was evaporated under reduced pressure to give a colorless residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C25H22ClN3O4 463.13 observed m/e: 464.16 (M+H)+ (Rt 1.21/2 min); 1H NMR δ (ppm) (CD3OD): 8.10 (s, 1H), 7.78 (ab qt, J=8.2 Hz, J=11.5 Hz, 4H), 7.72 (d, J=8.0 Hz, 2H), 7.50 (t, J=7.8 Hz, 2H), 7.40 (t, J=7.5 Hz, 1H), 5.62 (qt, J=5.0 Hz, 1H), 5.02 (t, J=5.3 Hz, 1H), 4.65 (t, J=4.8 Hz, 1H), 4.18 (dd, J=4.4 Hz, J=10.6 Hz, 1H), 4.14 (dd, J=5.4 Hz, 10.6 Hz, 1H), 3.99-4.03 (m, 1H), 3.98 (t, J=7.2 Hz, 1H), 3.64 (t, J=8.3 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:17][CH2:18][C:19]([OH:40])=[O:20])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(OCc1ccccc1)C1(N(CCCO)S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of the crude 1-[[4-(4-fluorophenoxy)benzenesulfonyl]-(3-hydroxypropyl)amino]cyclopentanecarboxylic acid benzyl ester (235 grams) in acetone (2 L) was cooled in an ice bath and treated with Jones reagent (about 200 mL) until an orange color persisted. The mixture was stirred from 0° C. to room temperature over 1 hour. After quenching excess oxidant with isopropanol (10 mL), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated to afford a solid which was triturated with a mixture of diethyl ether and hexane to provide 1{(2-carboxyethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentane carboxylic acid benzyl ester as a white solid (147 grams).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[F-:15].[K+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([F:15])(=[O:13])=[O:12]
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [K+]
Product: O=S(=O)(F)c1ccc2ccccc2c1
Yield: 92 %

Procedure:
2-Naphthalenesulfonyl fluoride was prepared from 2-naphthalenesulfonyl chloride and potassium fluoride as described in Example 1. A product with mp 85°-86° C (literature 86°-88° C; W. Davies and J. H. Dick, J. Chem. Soc., 2104, 1931) was obtained in 92% yield. The chemical analysis NMR and IR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:33])=[CH:12][N:11]=1>>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([O:32][C:23]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[N:11][C:10]([NH2:9])=[N:15][CH:14]=3)=[C:17]([F:33])[CH:18]=2)[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Product: Nc1cc(Oc2cc(C(F)(F)F)ccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)ncn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 555 using 6-chloropyrimidin-4-amine and 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.60-8.54 (d, J=1.3, 2H), 8.11-8.07 (d, J=0.9, 1H), 7.82-7.69 (m, 2H), 7.60 (s, 1H), 7.59-7.52 (m, 1H), 7.47-7.36 (m, 2H), 5.95-5.88 (d, J=0.9, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)([O-:8])=[O:7].[BH3-]C#N.[Na+]>CO>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:5][CH2:4][C:3]#[N:2])([O-:8])=[O:7]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#CCNCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
2-aminoacetonitrile hydrochloride salt (3.67 g, 39.7 mmol) was added to a solution of 2-nitrobenzaldehyde (5.00 g, 33.1 mmol) dissolved in anhydrous MeOH (30 mL). The reaction was stirred at room temperature for 5 minutes to achieve solution. NaCNBH3 (2.08 g, 33.1) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then diluted with EtOAc (50 mL). The organics phase was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated to give 4.20 g (22.0 mmol, 66% yield) of 2-(2-nitrobenzylamino)acetonitrile (1) as a tan oil 4.20 g (22.0 mmol, 66% yield). The material was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:30]1[CH:31]=[CH:32][C:33]2[N:34]=[CH:35][N:36]=[C:37]([O:40][CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[C:38]=2[N:39]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])(=[O:10])=[O:11])=[CH:6][C:5]([C:30]2[CH:31]=[CH:32][C:33]3[N:34]=[CH:35][N:36]=[C:37]([O:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:38]=3[N:39]=2)=[CH:4][N:3]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(OC4CCOCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.02 g, 0.075 mmol) (Intermediate 3), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.032 g, 0.075 mmol), sodium bicarbonate (0.151 ml, 0.151 mmol) and PdCl2(dppf)-CH2Cl2Adduct (6.15 mg, 7.53 μmol) in dioxane (0.376 ml) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.02 g, 50%) as a yellow solid.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15](Br)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Temperature: 80 °C

Procedure:
A mixture of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine (20 mg, 0.044 mmol) and phenylboronic acid (6.9 mg, 0.057 mmol) in DME (1 mL) was prepared in a sealed tube and purged with N2. Tetrakis(triphenylphosphine) palladium(0) (0.002 mmol) was added, and the reaction tube sealed and heated at 80° C. overnight. After cooling, the reaction mixture was diluted with EtOAc, washed with 1N NaOH and brine, dried (MgSO4), and concentrated. The residue was purified by preparative TLC (40% EtOAc/hexanes) to afford N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (s, 1H), 7.52-7.36 (m, 5H), 7.10 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 and 8.7 Hz), 6.87 (dd, 1H, J=2.4 and 8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.7 Hz), 4.23-4.20 (m, 8H); LCMS: ret. time: 25.38 min.; purity: 100%; MS (m/e): 455 (MH+).