Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>>[CH:19]1([CH2:18][O:17][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][C:12]([C:13]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[OH:29])=[O:15])=[CH:11][N:10]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-fluorophenyl)-6-cyclopropylmethoxy-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 385.2 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[N:12]([CH3:24])[CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([Cl:23])=[N:17]1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[ClH:23].[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[N:12]([CH3:24])[CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: CN(CCCn1nc(Cl)ccc1=O)C1COc2ccccc2O1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCCn1ncccc1=O)C1COc2ccccc2O1
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
A solution containing 30 g (0.08 mole) of 2-[3-(benzo[1,4]dioxan-2-yl-methylamino)-1-propyl]-6-chloro-3(2H)-pyridazinone hydrochloride (prepared as described in Example 2), 600 ml of absolute ethanol and 6.2 g of powdered sodium hydroxide is hydrogenated in the presence of 3 g of 5% palladium-on-charcoal catalyst under atmospheric pressure and at room temperature. After ceasing of the hydrogen uptake, the catalyst is filtered off, washed 3 times with 20 ml of absolute ethanol each and the filtrate is evaporated under reduced pressure. The residue is boiled with 50 ml of absolute isopropanol for 5 minutes and then filtered. The pH value of the filtrate is adjusted to 4 by adding 25% ethanolic hydrogen chloride solution under stirring and cooling with ice. The mixture is kept at 4° C. overnight, the crystalline precipitate is filtered off, washed with ice-cool absolute ethanol and dried to give 17 g (63% yield) of the aimed product, m. p. 131°-132° C. After recrystallization from ethanol, the hydrochloride melts at 133°-136° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1.[O:20]1[C@H:22]2[CH2:23][C@@:24]3([CH3:46])[CH:28]([CH:29]4[CH2:30][C@H:31]([F:40])[C:32]5[C@@:37]([CH3:38])([C@:21]124)[CH:36]=[CH:35][C:34](=[O:39])[CH:33]=5)[CH2:27][C@@H:26]([CH3:41])[C@:25]3(O)[C:42]([OH:44])=[O:43].Cl>CN(C=O)C>[O:20]1[C@H:22]2[CH2:23][C@@:24]3([CH3:46])[CH:28]([CH:29]4[CH2:30][C@H:31]([F:40])[C:32]5[C@@:37]([CH3:38])([C@:21]124)[CH:36]=[CH:35][C:34](=[O:39])[CH:33]=5)[CH2:27][C@@H:26]([CH3:41])[C@:25]3([O:18][C:17]([C:14]1[CH:13]=[N:12][C:11]([CH3:10])=[CH:16][N:15]=1)=[O:19])[C:42]([OH:44])=[O:43]
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)O
Reactant: Cc1cnc(C(=O)O)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N,N-Diisopropylethylamine (2.3 mL) is added to a cooled (0° C.) solution of 5-methylpyrazine-2-carboxylic acid (736 mg) in DMF (7 mL), followed by O-(7-azabenzotriazo-1-lyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2.26 g). The suspension is stirred at room temperature for 10 minutes, then a solution of (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (2 g) in DMF (7 ml) is added. After 2 hours, the reaction mixture is added dropwise to a solution of 1M HCl. The product is collected by filtration, washed repeatedly with water and dried to yield 5-methyl-pyrazine-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-carboxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected H-NMR signals (CDCl3) δ 0.95 (3H, d), 1.10 (3H, s) 1.40 (3H, s), 2.65 (3H, s).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[C:19]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([I:1])=[N:3]2)[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.12 g, 0.016 mol) in N,N-dimethylformamide (50 mL) was reacted with 60% sodium hydride in oil (0.75 g, 0.019 mol) at ambient temperature. The mixture was stirred for 15 minutes, and 2-chloro-4-nitropyridine (3.00 g, 0.019 mol) was added. The mixture was heated at 100° C. for 18 hours. The mixture was cooled to room temperature and the precipitate was filtered, washing with N,N-dimethylformamide (20 mL), and then slurried in ethyl acetate (50 mL) for four hours. The solid was filtered and dried in vacuo to give 1-(2-chloro-4-pyridyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.39 g, 0.009 mol) as a tan solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18].O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18]
Reactant: CSc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CSc1ccccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 25 h
Yield: 97.8 %

Procedure:
A solution of 2-fluoro-2′-methylthio-5-nitrobiphenyl (6.00 g, 22.8 mmol) in tetrahydrofuran (50 ml) and ethanol (50 ml) was treated with tin(II) chloride dihydrate (25.70 g, 113.9 mmol) and the mixture was stirred at ambient temperature for 25 h. The solvent was evaporated and the residue stirred with 2N sodium hydroxide solution (240 ml) for 18 h. The resulting suspension was extracted with dichloromethane (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel eluting with 35% ethyl acetate in isohexane to afford 2-fluoro-2′-(methylthio)biphenyl-5-ylamine as a white solid (5.20 g, 98%): δH (360 MHz, CDCl3) 2.39 (3H, s), 6.60 (1H, dd, J 6 and 3), 6.64-6.68 (1H, m), 6.94 (1H, t, J 9), 7.19-7.20 (2H, m), 7.30 (1H, d, J 8), 7.33-7.37 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]1[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:14]2=[N:15][C:16]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:18]=[C:13]2[CH2:12][CH2:11]1)[CH3:2].N#N>CCO>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:14]2=[N:15][C:16]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:18]=[C:13]2[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CCC=CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Agent: N#N
Solvent: CCO
Product: CCOC(=O)CCCCCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 6-(6-ethoxy-6-oxohex-2-enyl)-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 3) (88 mg, 0.158 mmol) in EtOH (3 ml) was degassed with N2 and treated with 10% Pd(C) (1.685 mg, 0.016 mmol). The resulting black suspension was stirred at room temperature under an atmosphere of hydrogen for 16 hours. The resulting mixture was filtered through a pre-packed 2.5 g Celite® column eluting with EtOH. The filtrate concentrated under reduced pressure to afford the titled compound as a yellow oil:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(Cl)Cl.O>COCCOC.O.CCO.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>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3-c3ccccc3)c(C)nc12
Temperature: 160 °C
Yield: 53.2 %

Procedure:
50 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.11 mmol), 40 mg of phenylboronic acid (0.33 mmol) and 0.27 ml of 2 M Na2CO3aq. (0.55 mmol) are put in 2.5 ml of DME/water/EtOH=7/3/1. N2 gas is bubbled in the mixture for 20 min and 20 mg of Pd(PPh3)4 (0.017 mmol) is added. The vial is sealed and heated at 160° C. for 30 min in Microwave. The reaction mixture are added CH2Cl2 and water and the organic layer is separated, washed with brine, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=10:1) to give 27 mg of the title compound. Yield 54% mass spectrum (m/e): 462 (M+1). δ 8.29 (m, 1H), 7.60 (m, 2H), 7.44 (m, 1H), 7.22 (m, 1H), 6.70 (s, 1H), 3.90 (t, J=4.6 Hz, 4H), 3.64 (t, J=5.0 Hz, 4H), 3.36 (m, 1H), 2.52 (s, 3H), 2.09 (s, 3H), 1.86 (m, 4H), 0.90 (t, J=7.4 Hz, 6H).
Reaction SMILES: C1C=[N+]([C@@H]2O[C@H](C[O:13][P:14]([O:17]P(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-:16])=[O:15])[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[CH:45]1[N:46]=[C:47]([NH2:88])[C:48]2[N:53]=[CH:52][N:51]([C@@H:54]3[O:58][C@H:57]([CH2:59][O:60][P:61]([O:64][P:65]([O:68][CH2:69][C@H:70]4[O:74][C@@H:73]([N:75]5[CH:80]=[C:79]([C:81]([NH2:83])=[O:82])[CH2:78][CH:77]=[CH:76]5)[C@H:72]([OH:84])[C@@H:71]4[OH:85])([OH:67])=[O:66])([OH:63])=[O:62])[C@@H:56]([OH:86])[C@H:55]3[OH:87])[C:49]=2[N:50]=1.C([O-])=O.C([O-])=O.[Na+].OP([O-])(O)=O.[K+]>O.C(#N)C>[P:14]([O-:17])([O-:16])([O-:15])=[O:13].[CH:45]1[N:46]=[C:47]([NH2:88])[C:48]2[N:53]=[CH:52][N:51]([C@@H:54]3[O:58][C@H:57]([CH2:59][O:60][P:61]([O:64][P:65]([O:68][CH2:69][C@H:70]4[O:74][C@@H:73]([N:75]5[CH:80]=[C:79]([C:81]([NH2:83])=[O:82])[CH2:78][CH:77]=[CH:76]5)[C@H:72]([OH:84])[C@@H:71]4[OH:85])([OH:67])=[O:66])([OH:63])=[O:62])[C@@H:56]([OH:86])[C@H:55]3[OH:87])[C:49]=2[N:50]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C[O-]
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CC#N
Product: O=P([O-])([O-])[O-]

Procedure:
Reagents: Lyophilized nicotinamide adenine dinucleotide-diaphorase (NAD-diaphorase), p-iodonitortetrazolium violet (INT), formate dehydrogenase, and sodium formate are all obtained from Sigma Chemical Co. Acetonitrile, Na2HPO4, and KH2PO4 are of analytic grade, and reverse osmosis-deionized water is used. Phosphate buffer (100 mmol/L, pH 6.0) is prepared by mixing 100 mmol/L KH2PO4 and 100 mmol/L Na2HPO4 (5:1). Buffered NAD-diaphorase is prepared by adding 150 ml of buffer to one bottle of lyophyhlized NAD-diaphorase (Sigma). Buffered NAD-diaphorase-INT is prepared by addition of 140 mg INT (Sigma) to 140 ml of buffered NAD-diaphorase, and recombinant P. pastoris FDH is lyophilized. Specific activity of the P. pastoris FDH is 0.4 to 1.0 unites/mg solid (0.4 to 1.8 units/mg protein). Portions (5 to 15 mg) are weighed into 1.5 ml glass vials and stored at −70° C. One vial is used for each batch analysis. Each is reconstituted with about 100 to 200 μl/mg buffered NAD-diaphorase (5° C.) and kept in an ice bath during analysis. Serum and aqueous standards (10 ml each) are supplemented with stock aqueous sodium formate solutions containing 10.0 or 1.0 g/L to produce concentrations ranging from 0 to 400 mg/L with less than 1% volumetric alteration of the matrix. Working reagent and final reaction (cuvette) concentrations are shown in the table, below.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=2)=[CH:5][C:4]=1[CH3:25])=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[CH:10]=3)=[CH:5][C:4]=2[CH3:25])[S:26]1
Reactant: Cc1cc(-c2cccc(CN(C)C(=O)OC(C)(C)C)c2)ccc1C=O
Reactant: O=C1CSC(=O)N1
Product: Cc1cc(-c2cccc(CN(C)C(=O)OC(C)(C)C)c2)ccc1C=C1SC(=O)NC1=O

Procedure:
In a manner similar to that of Example 1(f) by reacting 1 g (2.9 mmol) of tert-butyl (4′-formyl-3′-methylbiphenyl-3-ylmethyl)-N-methylcarbamate with 350 mg (2.9 mmol) of 2,4-thiazolidine dione, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (6/4), 740 mg (57%) of the expected product are obtained in the form of a yellow oil
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([CH3:20])[CH2:7][CH:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)O.S(=O)(=O)(O)O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:21]([CH:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[CH2:7][N:6]([CH3:20])[CH2:5]2)=[CH:22][CH:23]=1
Reactant: CN(Cc1cccc(Br)c1)CC(O)c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CN1Cc2cc(Br)ccc2C(c2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
To a solution of Compound 16 (˜110 mmol) in methylene chloride (1.0 L) was added concentrated sulfuric acid (30.0 mL, 0.56 mol) and the mixture was stirred at 0° C. for 3 h. The reaction was quenched by adding 6 N NaOH until the pH was ˜9, and the aqueous phase was extracted with additional methylene chloride (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (9:1 to 8:1 hexanes/ethyl acetate) to afford Compound 17 (15.79 g, 41% over 3 steps) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.82-7.70 (m, 3H), 7.66 (s, 1H), 7.49-7.41 (m, 2H), 7.28-7.20 (m, 2H), 7.16 (dd, J=8.3, 2.3 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.37 (dd, J=7.5, 6.5 Hz, 1H), 3.75 (d, J=15.3 Hz, 1H), 3.62 (d, J=15.3 Hz, 1H), 3.08 (ddd, J=11.5, 6.0, 1.0 Hz, 1H), 2.64 (dd, J=11.5, 8.5 Hz, 1H), 2.43 (s, 3H). The undesired 5-bromo isomer was also obtained (11.91 g, 30% over 3 steps).
Reaction SMILES: 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.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([OH:54])=O)=[CH:40][CH:41]=2)[N:36]=1.[NH2:55][CH:56]([CH2:62][C:63]1[CH:64]=[N:65][C:66]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])=[CH:67][CH:68]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([NH:55][CH:56]([CH2:62][C:63]3[CH:64]=[N:65][C:66]([C:69]4[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=4[F:76])=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:54])=[CH:40][CH:41]=2)[N:36]=1
Reactant: CN(C)C(=O)C(N)Cc1ccc(-c2cccc(F)c2F)nc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
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: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4ccc(-c5cccc(F)c5F)nc4)C(=O)N(C)C)ccc23)CC1
Reaction time: 2 h
Yield: 17.4 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 2-amino-3-[6-(2,3-difluorophenyl)pyridin-3yl]-N,N-dimethylpropanamide (20 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified with out workup by RP-HPLC (pH=2) to afford the desired compound (0.003 g, 10%) as an amorphous white solid TFA salt. Analytical LCMS (M+H)+: m/z=575.0.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C1COCC1>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[CH:7][N:6]=1
Reactant: COc1ncc(Br)c(OC)n1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COc1ncc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)n1
Temperature: 0 °C
Yield: 75 %

Procedure:
To a stirred solution of 5-bromo-2,4-dimethoxypyrimidine (400 g, 1.826 mol) in anhydrous THF (3 L) under argon and cooled down to 0° C. was added dropwise TurboGrignard (1.821 L, 2.367 mol). The resulting mixture was stirred at 0° C. until exothermic ceased then, allowed to warm up and stir at RT for 30 min. A solution of di-tert-butyl azodicarboxylate in anhydrous THF (1 L) was added dropwise to the mixture and the reaction was stirred at RT for 1 hr. The reaction was slowly quenched with a saturated aq. NH4Cl solution (2 L), diluted with EtOAc (2 L) and water (2 L) and both phases separated. The aq. phase was extracted with EtOAc (3 L), combined organic layers were washed with brine (3 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting yellow oil was dissolved in Hexane (3 L) and the suspension was stirred at 0° C. for 3 hr, filtrated off and dried to afford a first batch of white crystals. The mother liquor was concentrated under reduced pressure and purified to afford a second batch of white crystals. The two batches were combined to afford the title product (507 g, 1.369 mol, 75% yield) as white crystals. tR: 1.03 min (LC-MS 1); ESI-MS: 371 [M+H]+, ESI-MS: 369 [M−H]− (LC-MS 1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Br)c2)c(N)c2ccc(Cl)cc21
Product: CS(=O)(=O)Nc1c(C(=O)c2cccc(Br)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 38 from ethyl 3-amino-2-(3-bromobenzoyl)-6-chloro-1H-indole-1-carboxylate (step 1) and methanesulfonyl chloride.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[CH3:13][Mg]Br>O1CCCC1>[O:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH3:13])[CH2:11][CH2:10]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)C1CCOCC1
Temperature: -25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (3.5 g, 20.2 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium bromide (12 mL, 36.4 mmol) at −65° C. under N2. The reaction was stirred at −65-15° C. for 3 hrs. Then the mixture was quenched by water, extracted with ethyl acetate. The organic layer was washed with 1 M HCl, saturated aqueous NaHCO3 and concentrated in vacuo to give 1-(tetrahydro-2H-pyran-4-yl)ethanone (1.9 g, 73.6%) as a yellow oil. 1H NMR (CDCl3, 400 M Hz) δ 4.01-3.97 (m, 2H), 3.45-3.39 (m, 3H), 2.57-2.49 (m, 1H), 1.80-1.71 (m, 2H), 1.70-1.62 (m, 2H).
Reaction SMILES: ClC1C=CC(C2CC(=O)C3C(=CC=CC=3)O2)=CC=1.Cl.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([CH:25]2[CH:34]([CH2:35]N(C)C)[C:33](=[O:39])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:26]2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH:25]2[C:34](=[CH2:35])[C:33](=[O:39])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:26]2)=[CH:40][CH:41]=1
Reactant: CN(C)CC1C(=O)c2ccccc2OC1c1ccc(Cl)cc1
Agent: Cl
Agent: O=C1CC(c2ccc(Cl)cc2)Oc2ccccc21
Product: C=C1C(=O)c2ccccc2OC1c1ccc(Cl)cc1
Yield: 35.8 %

Procedure:
In a similar manner as described in Example 1, 10 g of 4'-chloro flavanone, as described in Bull. Soc. Chim. France 2248 (1963), was converted to 4.0 g of crude 4'-chloro-3-dimethylaminomethyl flavanone hydrochloride. The hydrochloride salt was recrystallized twice from acetone to give 1.1 g of crystals, m.p. 147°-149° C.
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=O)=O)C1C=CC=CC=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>CN1CCCC1=O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:19]1[CH2:20][C:14]2[C:15](=[N:16][C:11]([NH:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]3)=[N:12][CH:13]=2)[N:17]([CH2:29][C:30]([F:32])([F:31])[F:33])[C:18]1=[O:28]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C1N(c2ccccc2Cl)Cc2cnc(S(=O)(=O)Cc3ccccc3)nc2N1CC(F)(F)F
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccccc2Cl)Cc2cnc(N[C@H]3CC[C@H](O)CC3)nc2N1CC(F)(F)F
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
7-Benzylsulfonyl-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (300 mg, 0.604 mmol), trans-4-aminocyclohexanol (208 mg, 3 equivalents) and 1-methyl-2-pyrrolidinone (0.3 mL) were heated with stirring at 110° C. for 20 minutes, at which time it was cooled to room temperature. The residue was purified using preparative thin layer chromatography using ethyl acetate as eluant, to give 155 mg of 3-(2-chlorophenyl)-7-(trans4-hydroxycyclohexylamino)-1-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white powder.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:18]([N:20](CC)CC)C.CN.O>C1COCC1>[CH3:18][NH:20][S:13]([C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][N:4]2[C:1](=[O:3])[CH3:2])=[CH:8][C:9]=1[Br:17])(=[O:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
To a slurry of 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride (see Preparation 43) (0.40 g, 1.2 mmol) in THF (3.38 mL) was added triethylamine (0.660 mL, 4.73 mmol) and 40% methylamine in water (0.18 mL, 2.4 mmol). The reaction was heated to reflux and stirred for 1.5 h, then cooled and concentrated. The residue was slurried in hot MeOH and filtered under vacuum washing with MeOH. The solid was dried in vacuo at 40° C., to give 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonic acid methylamide (0.33 g, 85%) as a colourless solid. This product (320 mg, 1.0 mmol) was slurried in 1,4-dioxane (0.98 mL) and concentrated hydrochloric acid (0.72 mL), heated to 100° C. for 1.5 h, then cooled to ambient temperature solvent removed in vacuo. The pH was adjusted to 7 with 1 M aqueous NaOH and the resulting precipitate collected by vacuum filtration, washed with water and dried in vacuo at 40° C., to give the title compound (0.176 g, 62%) as a beige solid; MS: [M+H]+ 291