Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)CCc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)CCc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of the product of Example 7A (505 mg, 2.447 mmol) in THF (19 mL) at 0° C. was added a 1M solution (in THF) of lithium aluminum hydride (12.2 mL, 12.237 mmol) dropwise. After completion of addition the ice bath was removed and the reaction was stirred at room temperature for 1 hour under nitrogen atmosphere. Then, in succession, was added water (183 μL), 15% NaOH solution (183 μL), and water (548 μL). The reaction stirred for an additional 15 minutes before it was filtered and washed with THF. The filtrate was then concentrated under reduced pressure to obtain 4-(4-hydroxymethyl-phenyl)butan-2-ol as a brown oil (314 mg, 71% yield). Then to a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (234 mg, 1.155 mmol) in THF (45 mL) was added 4-(4-hydroxymethylphenyl)butan-2-ol (312 mg, 1.732 mmol), triphenylphosphine (454 mg, 1.732 mmol), and then diisopropyl azodicarboxylate (DIAD, 335 μL, 1.732 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Thin layer chromatography (100% ethyl acetate) indicated consumption of the pyridazinone starting material and the reaction was concentrated. The crude material was purified by flash column chromatography (4:1 hexane:ethyl acetate to 100% ethyl acetate) to obtain a clear oil (200 mg, 48% yield). 1H NMR (600 MHz, CDCl3); δ 7.73 (s, 1H), 7.32 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 5.30 (s, 1H), 5.27 (s, 2H), 3.83 (m, 1H), 2.80-2.76 (m, 1H), 2.71-2.66 (m, 1H), 1.63 (s, 9H), 1.23 (d, 3H, J=6.2); 13C(CDCl3 159.3, 153.9, 143.2, 132.5, 129.2, 127.6, 125.4, 150 MHz): δ HRMS calcd for C118.5, 73.4, 67.6, 66.6, 40.9, 32.0, 28.1, 23.9.19H25ClN2O3: 365.162647, found 365.1624.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C=P(C)(C)C)#N.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: OCCOCc1ccccc1
Agent: CP(C)(C)=CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1CCOCc1ccccc1
Temperature: 20 °C
Yield: 88.1 %

Procedure:
94 μl (0.657 mmol) of 2-benzyloxyethanol and 50.4 mg (0.438 mmol) of (cyanomethylene)trimethylphosphorane (Tet. Lett., 1996, 37, 2459-2462) are added to a solution of 68 mg (0.329 mmol) of ethyl 5-fluoro-1H-indole-2--carboxylate in 2 ml of toluene, stirred at 20° C. The reaction mixture is heated at 110° C. for 12 hours and then concentrated under reduced pressure, taken up in 20 ml of ethyl ether, filtered over a celite buffer and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC, elution being carried out with a mixture of water, acetonitrile and trifluoroacetic acid. 99 mg of a yellow oil are thus isolated.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](I)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.O.[C:34]([O:37][CH2:38][CH3:39])(=[O:36])C>CN(C1C=CN=CC=1)C.C(O)C.[Pd]>[CH2:38]([O:37][C:34]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:36])[CH3:39]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2I)CC1
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(OC2CCNCC2)ccc2cnccc12

Procedure:
A solution of 200 mg (0.44 mmol) 4-(5-iodo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (12), 107 mg (0.88 mmol) of DMAP, 4.7 mg (0.1 eq) of Pd on charcoal (10%), 150 μL (0.88 mmol) of triethyl amine and 58 mg (0.22 mmol) of Mo(CO)6 in 3 mL of ethanol was heated to 135° C. for 1 h in a microwave reactor (CEM Discovery). Then water and ethyl acetate were added and the mixture was filtered through a Celite cartridge. After removal of the solvents the remainder was subjected to preparative HPLC to give the 7.4 mg Boc-protected intermediate. To remove the Boc group the intermediate was treated with 2 mL 5-6 N HCl in isopropanol at room temperature for 2 h. Purification by preparative HPLC gave 2.5 mg of compound 30 as TFA salt.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:23]1[C:27]2[CH:28]=[CH:29][C:30](B(O)O)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:3]=[C:4]([C:9]4[N:13]5[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]5=[N:11][CH:10]=4)[CH:5]=[CH:6][C:7]=3[F:8])=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc5c(c4)OCO5)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and benzo[1,3]dioxole-5-boronic acid were coupled in the same way as in Example 30 to give 2-{3-[3-(benzo[1,3]dioxol-5-yl)-4-fluorophenyl]-8-fluoroimidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (8 mg, 4%): m/z (ES+) 409 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2].[CH3:11][S:12](O)(=[O:14])=[O:13].P(Cl)(Cl)(Cl)=O>>[CH2:1]([C:3]1[C:4]([CH2:9][CH3:10])=[C:5]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccccc1CC
Reactant: CS(=O)(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cccc(S(C)(=O)=O)c1CC
Temperature: 90 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
An isomeric mixture of diethyl benzene (268.44 g, 2.0 moles), anhydrous methane sulfonic acid (96.1 g, 1.0 mole) and phosphorus oxychloride (25.6 g, 2.17 moles) were heated at 90° C. with stirring for 8 hours. Treatment of the reaction mixture after cooling was the same as in Example 1 and 25 g (12% yield) of methyl diethylphenyl sulfone was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(4-fluorophenyl)quinazoline-4-carboxylic acid (100 mg, 0.37 mmol, 1.00 equiv), 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (88 mg, 0.41 mmol, 1.10 equiv), oxolane (10 mL), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 170 mg, 0.45 mmol, 1.20 equiv) and DIEA (241 mg, 1.87 mmol, 5.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 1×100 mL of saturated aqueous sodium bicarbonate, 1×100 mL of ammonia (5%) and 1×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1) or purified by Prep-HPLC with the following conditions (Sunfire Prep): Column, C18 Sum 15*190 mm; mobile phase, A: HCOOH B: CH3CN; Detector, UV 254 nm. This resulted in 30 mg (19%) of 2-[[2-(4-fluorophenyl)quinazolin-4-yl]carbonyl]-5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.90 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.39 and 4.92 (2s, 2H), 6.30-6.33 (m, 0.4H), 6.69-6.78 (m, 1H), 6.90-6.92 (m, 0.6H), 7.36-7.44 (m, 2.7H), 7.69-7.79 (m, 1H), 7.86-7.97 (m, 1H), 8.06-8.17 (m, 2H), 8.53-8.61 (m, 2H), 8.69 and 8.73 (2s, 1H); 19F (282 MHz, DMSO-d6) δ −110.2; MS (ESI) m/z 430 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CO.[CH2:15](Cl)CCl>C(#N)C.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: ClCCCl
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cc(Br)cc(C=O)c1
Temperature: -10 °C
Reaction time: 20 h

Procedure:
6.2 g (27.1 mmol) of 3-bromo-5-formylbenzoic acid (J. Org. Chem., 2002, 67, 3548-3554) are dissolved in 110 ml of acetonitrile under argon. 330 mg (2.7 mmol) of 4-dimethylaminopyridine and 1.73 ml (54.2 mmol) of methanol are added thereto. The mixture is cooled to −10° C., and 6.23 g (32.5 mmol) of EDC are added. The mixture is slowly allowed to reach RT and is then stirred for 20 h. The solvent is then evaporated in vacuo, and the residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate (6:1)).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>C(#N)C>[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:17]4[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=4)=[CH:26][CH:25]=3)[C:3]=2[CH:11]=1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Solvent: CC#N
Product: Fc1ccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)cc1

Procedure:
4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and 4-(4-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.83 g); m/z 381 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:11]([N:13]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([N:13]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][CH2:25][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:26][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: C=Cc1ccc(N(CC)c2ccccc2)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(CC)c2ccccc2)cc1)(OCC)OCC
Temperature: 25 °C

Procedure:
Into a three-necked flask, 40 ml of toluene, 9.9 g (60 mmol) of triethoxysilane and 0.018 mmol of diplatinum (0) tris(tetramethyldivinyldisiloxane)in toluene were placed, and 20 ml of a toluene solution containing 7.6 g of 4-(N-ethyl-N-phenylamino)styrene was added dropwise with stirring at room temperature. After the addition was completed, the mixture was stirred at 70° C. for 3 hours, and then the solvent was removed under reduced pressure to obtain oily pale yellow 4-(N-ethyl-N-phenylamino)-[2-(triethoxysilyl)ethyl]benzene in an amount of 7.8 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[C:24]1(B(O)O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:32]4[C:33]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:29]=[CH:30][CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccc2ccccc12
Product: COc1cc2ncn(-c3nc(-c4cccc5ccccc45)c(C(=O)O)s3)c2cc1OC
Yield: 36.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 1-naphthaleneboronic acid (25.8 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-naphthalen-1-yl-thiazole-5-carboxylic acid (15.9 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.41 (br.s., 1 H); 8.85 (s, 1 H); 8.01-8.09 (m, 2H); 7.92 (dd, 1 H); 7.72 (dd, 1 H); 7.69 (s, 1H); 7.50-7.65 (m, 3H); 7.40 (s, 1 H); 3.84 (s, 3 H); 3.68 (s, 3 H). MS m/z 432 (M+1).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>>[CH2:21]([N:24]1[CH2:2][CH:3]2[CH:5]([C:4]2([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:6]1=[O:8])[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Product: C=CCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Yield: 100.6 %

Procedure:
Ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropanecarboxylate (Preparation 5, 1 g, 3.36 mmol) in allylamine (1.15 g, 20.1 mmol) was heated in a sealed tube at 150° C. for 16 h. After cooling the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product as a yellow oil (0.92 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>O>[C:9]1([S:15]([NH:18][C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[CH:3]=2)=[O:20])(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2cccc(NC(=O)NS(=O)(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5.65 g m-aminophenol in 45m-acetonitrile was added dropwise 9.5 g benzenesulphonylisocyanate such that the temperature was maintained at <40° C. The mixture was stirred for one hour at room temperature and allowed to stand overnight. To the reaction was then added 25ml water and 5.35 g 47% caustic soda and the reaction was heated to 55-60° C. To this was added, over two hours, 9.93 g p-toluenesulphonylchloride with simultaneous addition of 47% caustic soda so as to maintain the pH between 10 and 11. After two hours at 60° C. the reaction mass was neutralised with hydrochloric acid to produce a thick white precipitate of the desired product. This was isolated by filtration and washed with water to give after drying 21.1 g of product, melting point 162-170° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([OH:26])[CH2:4][C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:64][CH3:65])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[CH2:4][C@H:3]([OH:26])[C@@H:2]([NH:1][C:44](=[O:45])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[CH:42]([CH3:41])[CH2:64][CH3:65])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2ccnc3ccccc23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)CC)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
A solution containing the product from Example 5C (0.078 g, 0.171 mmol) in DMF (0.5 mL) was treated with the product from Example 4A (0.070 g, 0.205 mmol), EDAC (0.050 g, 0.261 mmol), HOBT (0.035 g, 0.259 mmol), and NMM (0.060 mL, 0.546 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, diluted sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.030 g, 23% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (m, 12 H), 1.00 (m, 2 H), 1.29 (m, 2 H), 1.49 (m, 3 H), 1.81 (m, 1 H), 2.65 (m, 5 H), 3.01 (m, 3 H), 3.54 (s, 3 H), 3.61 (m, 1 H), 3.75 (t, J=8.82 Hz, 1 H), 3.99 (d, J=11.03 Hz, 1 H), 4.13 (m, 2 H), 4.62 (d, J=7.35 Hz, 1 H), 4.80 (m, 2 H), 6.89 (d, J=9.56 Hz, 1 H), 6.98 (m, 5 H), 7.15 (m, 5 H), 7.32 (d, J=9.93 Hz, 1 H), 7.41 (d, J=4.41 Hz, 1 H), 7.66 (m, 2 H), 7.77 (t, J=6.99 Hz, 1 H), 8.06 (d, J=7.72 Hz, 1 H), 8.30 (d, J=8.09 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2N=C(C3N=C(C4CCCCC4)NC=3COC34CC5CC(CC(C5)C3)C4)SC=2)[CH:5]=1.Br[C:40]([Br:42])=O.C[OH:44]>>[CH3:1][O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:44])[CH2:40][Br:42])[CH:5]=1
Reactant: CO
Reactant: O=C(Br)Br
Reactant: COC(=O)c1cccc(-c2csc(-c3nc(C4CCCCC4)[nH]c3COC34CC5CC(CC(C5)C3)C4)n2)c1
Product: COC(=O)c1cccc(C(=O)CBr)c1

Procedure:
3-{2-[5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazol-4-yl]-thiazol-4-yl}-benzoic acid methyl ester. 3-(2-Bromo-acetyl)-benzoic acid methyl ester was prepared as described by Schmied (Schmied, Gading, Monatshefte Chem. 1953, 84, 491). A solution of this bromoketone (0.44 g, 1.7 mmol) and the thioamide from step c (0.52 g, 1.4 mmol) in methanol (10 ml) was heated under reflux for 5 h. The solvent was evaporated and the residue taken up in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (2×20 ml), brine (20 ml) then dried (MgSO4). The crude product was purified by flash chromatography (Silica, DCM/ethyl acetate 95:5-90:10). Yield 0.36 g (48%). 1H NMR (300 MHz, CDCl3) 9.25 (1H, br s), 8.64 (1H, s), 8.16 (1H, d), 8.01 (1H, d), 7.51 (2H, m), 5.17 (2H, s), 3.95 (3H, s), 2.79 (1H, m), 2.20 (3H, br s), 2.07 (2H, m), 1.90-1.36 (20H, m).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[S:23][CH:24]=[C:25]([CH2:26]OCOC)[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.Cl.N12CCCN=C1CCCCC2.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[N:60]([CH2:26][C:25]1[C:20]2[S:19](=[O:31])(=[O:32])[N:18]=[C:17]([C:8]3[C:7](=[O:33])[N:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:22][C:21]=2[S:23][CH:24]=1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 97.1 %

Procedure:
To 1-[(cyclopropylmethyl)amino]-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}quinolin-2(1H)-one (384.7 mg, 0.78 mmol) was added a solution of hydrogen chloride in dioxane (4N, 7.8 mL) at 0° C. The solution warmed to room temperature and stirred for 5.5 hours and concentrated under reduced pressure. This solid was suspended in dichloromethane (7.8 mL) and to the suspension was added 1,8-diazabicyclo[5.4.0] undec-7-ene (0.6 mL, 4.01 mmol) and diphenylphosphoryl azide (0.85 mL, 3.94 mmol) at room temperature and stirred overnight. The solution was concentrated in vacuo. The residue was purified by chromatography, eluting with 1% triethylamine/dichloromethane to give a triethylamine salt of 3-[7-(azidomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (357 mg, 79%). MS (ESI−) m/z 470 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.22 (m, 2 H) 0.46 (br d, J=7.35 Hz, 2 H) 1.01 (m, 1 H) 4.52 (s, 2 H) 5.98 (t, J=6.62 Hz, 1 H) 7.24 (s, 1 H) 7.40 (m, 1 H) 7.56 (m, 1 H) 8.05 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), isoamylamine (0.147 g, 1.68 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.225 g, 50%): TOF MS ES+ 333.2 (M+H)+, HRMS calcd for C17H22N4O2F 333.1727 (M+H)+, found 333.1714, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.1 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[N:28][N:27]=1.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:25][C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: Cn1nnnc1CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C(=N\OCc1nnnn1C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 154.7 %

Procedure:
17.7 g of ethyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are suspended in 320 ml of acetonitrile, treated successively with 27.6 ml of N-ethyldiisopropylamine, 16 g of 5-chloromethyl-1-methyl-tetrazole and 24 g of sodium iodide and the mixture is stirred at room temperature for 12 hours. The mixture is subsequently diluted with 1.5 l of ethyl acetate, washed three times with 500 ml of water each time, dried over magnesium sulphate and concentrated. There are obtained 39.6 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-methyl-1H-tetrazol-5-yl)methoxy]imino]-acetate as an oil which is used directly.