Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1>CN(C=O)C>[CH3:26][C:27]1[C:31]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:30]([CH3:35])[O:29][N:28]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3,5-dimethylisoxazole-4-boronic acid (CAS RN 16114-47-9) and using DMF as reaction solvent. Light brown solid (20%). MS (ESI): m/z=444.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)C=CC1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C)c1C1C(=O)CCC1=O
Temperature: 90 °C

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)cyclopent-4-ene-1,3-dione (described in WO 2010/089210) (50 g, 0.18 mol) in acetic acid (2000 ml) at 25-30°C. is added zinc powder (82.3 g, 1.26 mol). The resulting suspension is heated to 90°C. for 2 hours, followed by cooling to room temperature then filtration through a bed of diatomaceous earth. The residue is washed with methanol (100 ml×2) and the solution is concentrated in vacuo. Distilled water is added and the crude product is extracted with ethyl acetate (500 ml×3). Organic fractions are combined then washed with distilled water, brine, then dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to afford 2-(4-bromo-2,6-dimethylphenyl)cyclopentane-1,3-dione. This material is used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([NH:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:15].CO.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)CNC(=O)c1c(O)c2ccccc2n(C)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)NCC(=O)O)c(=O)n(C)c2ccccc12

Procedure:
Methyl 2-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.94 g, 1.4 mmol), methanol (0.33 ml, 8.1 mmol) and triphenyl phosphine (0.94 ml, 4.1 mmol) were placed in a 50 mL round bottomed flask with 25 mL of THF. The flask was placed in an ice bath. Diethyl azodicarboxylate (0.64 ml, 4.1 mmol) was added dropwise. A white solid was filtered and this solid was purified by silica flash chromatography (0-3% MeOH/DCM) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH:8]=[N:9][OH:10])=[O:5].[CH3:16][OH:17].Cl.C([BH3-])#N.[Na+]>CO.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]([CH:16]=[O:17])[OH:10])=[O:5]
Reactant: CO
Reactant: O=C(NCC=NO)c1cccc(Cl)c1Cl
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Product: O=CN(O)CCNC(=O)c1cccc(Cl)c1Cl
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 2,3-dichloro-N-(2-hydroxyimino-ethyl)-benzamide (34.3 g, 0.14 mol) in MeOH (700 mL) under an argon atmosphere at 0° C. was added methyl orange (0.01 g) followed by a saturated solution of MeOH/HCl until a persistent red color was observed. Sodium cyanoborohydride (10.5 g, 0.17 mol) was added sequentially with saturated MeOH/HCl over 0.5 h. The reaction mixture was stirred an additional 1 h and the MeOH was removed in vacuo. The residue was partitioned between 3N HCl (300 mL) and dichloromethane (300 mL). The organic phase was extracted with 3N HCl (2×200 mL). The combined aqueous extracts were washed with dichloromethane, were basidified with cold dilute NaOH and were extracted (7×100 mL) with dichloromethane/MeOH (9:1). The combined organic extracts were washed with brine, were dried (Na2SO4) and were concentrated. The residue was diluted with ether (200 mL) and the precipitate collected by filtration to provide the title compound (11 g, 32%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.60 (dd, j=1.7 and 7.8 Hz, 1H); 7.41 (dd, j=1.7 and 7.6 Hz, 1H); 7.35 (t, j=7.7 Hz, 1H); 3.57 (t, j=6.2 Hz, 2H); 3.06 (t, j=6.2 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[NH:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16].C(N(CCC)C(COC(=O)CCNC(OC(C)(C)C)=O)=O)CC.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:6]1([O:5][C:3]([CH2:2][O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C(CCl)OC1CCCCC1
Agent: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)NCCC(=O)OCC(=O)OC1CCCCC1

Procedure:
This compound was prepared from cyclohexyl 2-chloroacetate and Boc-Beta-Ala-OH by an analogous method to 3-tert-butoxycarbonylamino-propionic acid dipropylcarbamoylmethyl ester (Int. AA step 1). Cesium carbonate was used in place of potassium carbonate; 1H NMR (400 MHz, DMSO-d6) δ 6.83 (1H, br s), 4.76-4.70 (1H, m), 4.62 (2H, s), 3.20-3.12 (2H, m), 2.53 (2H, under DMSO peak), 1.28-1.72 (2H, m), 1.68-1.60 (2H, m), 1.53-1.18 (15H, m).
Reaction SMILES: [CH3:1][OH:2].[OH-].[Na+].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](S(O)(=O)=O)[C:12]=3[C:11](=[O:25])[C:10]=2[CH:9]=[CH:8][CH:7]=1>O>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[C:13]([O:2][CH3:1])[CH:14]=[CH:15][CH:16]=3)[C:11](=[O:25])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: Nc1cccc2c1C(=O)c1cccc(S(=O)(=O)O)c1C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1C(=O)c1cccc(N)c1C2=O
Reaction time: 3 h
Yield: 80 %

Procedure:
40 parts by volume of methanol and 10 parts of sodium hydroxide are dissolved at the boil and 13.3 parts of 1-aminoanthraquinone-5-sulphonic acid are introduced into this solution at 80°C, over the course of 30 minutes, with vigorous stirring. The mixture is now stirred for a further 3 hours at 80°-85°C until only traces of starting material are still present according to chromatography. The mixture is now diluted with 50 parts of hot water and the product is filtered off, washed with boiling hot water until neutral and dried at 100°-120°C. 8.9 parts of 1-amino-5-methoxy-anthraquinone (80% of theory) are obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].[OH-].[K+:11]>O>[CH3:6][N:5]([CH2:4][C:2]([O-:3])=[O:1])[C:7]([NH2:9])=[NH:8].[K+:11]
Reactant: CN(CC(=O)O)C(=N)N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)[O-])C(=N)N

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 7.87 g (60 mmol) of creatine is dissolved in 600 ml of water. To this is added 72 ml of 1M potassium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, potassium 2-(1-methylguanidino)acetate, shown below.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.C([O-])(=O)C.[Na+]>CO.[Pd].O>[N:7]1[CH:2]=[CH:3][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[CH2:10][CH2:9]2)=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccncn3)CC2)CC1
Reaction time: 8 h

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (50 mg, 0.13 mmol, prepared as described for Example 13) and sodium acetate (11 mg, 0.13 mmol) were dissolved in methanol (1.3 ml), 10% palladium on carbon (14 mg) added and the solution stirred overnight under a hydrogen atmosphere. The solution was diluted with 4:1 water:saturated sodium bicarbonate (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 35% acetone:hexanes to yield the titled compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].Cl[C:19]([S:21]Cl)=[O:20]>C1(C)C=CC=CC=1.CCCCCC.CO>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:19](=[O:20])[S:21][N:8]=2)[CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)SCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1oc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ns1
Reaction time: 12 h
Yield: 29.7 %

Procedure:
3,5-Bis(trifluoromethyl)benzamide (60.5 g, 0.235 mol) and five equivalents of chlorocarbonylsulfenyl chloride (154 g, 1.175 mol) were heated in 600 ml of toluene at reflux, with stirring, for 12 hours. The crude product, a dark brown oil, weighed 77.5 g. After decolorization in hexane, the material was taken up in methanol and recrystallized three times to give 22.0 g (0.0699 mol, 29.75%) of pale gold solid, m.p. 61°-62.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23].Cl[CH2:25][C:26]#[N:27].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:25][C:26]#[N:27])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: N#CCCl
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(CC#N)C3=O)CC2)cc1C
Temperature: 70 °C

Procedure:
To a solution of (R)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (6.32 mmol, 2.0 g) and chloroacetonitrile (6.32 mmol, 0.48 g) in THF (50 mL) was added sodium hydride (60%, 9.48 mmol, 0.38 g) and heated to 70° C. for 30 min. The reaction was allowed to cool to ambient temperature and dried under vacuum. Flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate and provided the title compound as an off-white residue (1.1 g, 49% yield). Calculated molecular formula=C20H25N3O3=355.4406. found MS (ESI) m/e 356.1978 (M+H+); analytical RP-HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.591 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1csc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1csc2c(Cl)ncnc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3, 2.9 g, 18 mmol) in phosphorus oxychloride (18 mL) under N2 was heated at reflux for 1 hour. The resulting solution as allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with diethyl ether. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 4-chloro-7-methylthieno[3,2-d]pyrimidine (3.1 g, 96% yield) as a white solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CCCCCCC.CCOC(C)=O>[CH2:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: N#CCCCBr
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC1CCN(CCCC#N)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
In a 100 mL flask with a magnetic stirrer was placed 3 (2.3 g, 16.4 mmol), 4-bromobutyronitrile (2.4 g, 16.4 mmol), potassium carbonate powder (2.5 g, 18 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at rt for 5 h followed by addition of H2O (15 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic phases were evaporated to dryness to produce 3.9 of crude 4. The crude product was subjected to CC [eluent:heptane:EtOAc (1:1)] to give pure 4 (2.3 g, 87%). 1H NMR (CDCl3) δ0.82 (t, 3H), 1.191.37 (m, 9H), 1.64-1.75 (d, 2H), 1.84-2.01 (m, 4H), 2.39-2.54 (m, 4H), 2.89-2.97 (d, 2H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].BrCC(OC)OC.CCN(CC)CC>CN(C=O)C>[NH2:6][C@H:5]([C:4]([OH:11])=[O:3])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: COC(CBr)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
A solution containing L-leucine methyl ester hydrochloride (2.9 g, 16 mmol), 2-bromo-1,1-dimethoxy ethane (1.9 ml, 2.7 g, 16 mmol), NEt3 (6.7 ml, 48 mmol) and a catalytic amount of KI in DMF (190 ml) was stirred at 120° C. for 3 days. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with DCM. The organic layer was then washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (silica gel, EtOAc/P.E. 1:1) to afford compound of formula (III), where R=Leu side chain, as a yellow oil (1.2 g, 32% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].O>CC(C)=O>[C:23]1([CH:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1nn(C(C)c2ccccc2)c2ccccc12

Procedure:
To a solution of methyl 1H-indazole-3-carboxylate (2.0 g, 11.4 mmol) in acetone (50 mL), were added potassium carbonate (1.6 g, 11.4 mmol) and (1-bromoethyl)benzene (2.2 g, 11.9 mmol). Then the mixture was refluxed for 12 hours. The reaction mixture was concentrated to give a residue. To the residue was added water (50 mL), extracted with dichloromethane (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to afford two isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Br)[CH2:11][CH2:10]1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([C:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=3)=[CH:28][NH:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][N:35]2[CH2:36][CH:37]=[C:32]([C:27]3[C:26]4[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=4)[NH:29][CH:28]=3)[CH2:33][CH2:34]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C(=O)CCCCBr)CC1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CCCCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)CC1
Yield: 69.7 %

Procedure:
Following the same procedure reported in the Step 2 of EXAMPLE 13, the reaction of 1-(2-methoxyphenyl)-4-(5-bromovaleryl)piperazine (9.29 mmol) with 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3.54 mmol) and triethylamine (4.63 mmol) gave the alkylation product (1.21 g, 53%). mp: 78-81° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>CS(C)=O>[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][CH2:23][N:8]1[CH2:7][C@@H:6]2[CH2:12][O:13][CH2:14][CH2:15][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: BrCCC1OCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2CCC1OCCO1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol) in DMSO (7 mL), sodium tert-butoxide (127 mg, 1.324 mmol), and 2-(2-bromoethyl)-1,3-dioxolane (220 mg, 1.213 mmol) (200 mg, 56%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O3, 327.12. found 327.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][N:28]1[C:29](=[O:38])[C:30]2=[CH:37][CH:36]=[CH:35][CH:34]=[C:31]2[C:32]1=[O:33]
Reactant: OCc1cccs1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cccs1
Reaction time: 15 h
Yield: 13.3 %

Procedure:
To a suspension of 2-thiophenemethanol (4.15 mL, 43.64 mmol), triphenylphosphine (12.59 g, 48.01 mmol) and N-hydroxyphthalimide (7.83 g, 48.01 mmol) in THF (120 mL) at 0° C. was added dropwise diethylazodicarboxylate (7.56 mL, 48.01 mmol) in THF (20 mL). The reaction mixture was allowed to stir for 15 h after which the solvent was removed under vacuum to dryness. Et2O (50 mL) was added to triturate the triphenylphosphine oxide and diethylhydrazinedicarboxylate, which was filtered off and washed with a little Et2O. The ethereal solution was concentrated under vacuum to give a residue which was filtered through a pad of silica (eluting with EtOAc/PE, 3:7). Removal of the solvent under reduced pressure afforded N-(thiophen-2-ylmethoxy)phthalimide (1.50 g, 13%), as a pale yellow solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C12(PC34CC(CC3)CC4)CC(CC1)CC2>C(O)C.O.C(Cl)Cl.[Cl-].[Cl-].C(#N)C1C=CC=CC=1.C(#N)C1C=CC=CC=1.[Pd+2]>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:1]([OH:2])=[O:4]
Reactant: Clc1ccccn1
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: C1CC2(PC34CCC(CC3)C4)CCC1C2
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)c1ccccn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Sodium carbonate (3.34 g, 32 mmols), 2-chloropyridine (2.38 g, 21 mmols) and 40 ml of ethanol are placed in a glass autoclave. The autoclave is rinsed with nitrogen and heated to 100° C. A solution of palladium bis(benzonitrile) dichloride (161 mg, 0.42 mmols) and dinorbornylphosphine (420 mg, 1.90 mmols) in 2 ml of ethanol (prepared under argon) is added, and then 5 bars CO are applied. After 16 hours at 120° C., the mixture is allowed to cool. The reaction mixture is taken up in water and methylene chloride. The aqueous phase is separated, acidified with concentrated hydrochloric acid and concentrated. The residue is extracted with ethanol and, after filtration, the ethanol is distilled off in a vacuum. The solid is recrystallised from water/ethanol/acetone. Yield of title compound as the hydrochloride: 2.13 g (64%).
Reaction SMILES: [Br:1][C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:15]([O:17]C)=[O:16])=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=2[CH:3]=1.CO.C1COCC1.O.[Li+].[OH-]>O>[Br:1][C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][C:9]([C:15]([OH:17])=[O:16])=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Methyl 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 17 mg, 0.050 mmol) was suspended in a 1:1:1 mixture of MeOH/THF/water (0.6 ml). LiOH (39 mg) was added and the mixture stirred at room temperature for one hour. Water and 6NHCl was added and the resulting precipitate was filtered. The material was purified by preparative HPLC. Genevac evaporation provided 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid as a solid (2.1 mg, 13% yield). LCMS (ES): >95% pure, m/z 324 [M]+, 326[M+2]+; 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.75 (dd, J=1.6, J=8.0, 1H), 7.90 (d, J=8.4, 1H), 8.03 (d, J=1.6, 1H), 12.06 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Cl:5][C:6]1[C:11](F)=[C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=[CH:8][C:7]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27]>CN1C(=O)CCC1.CO.C(Cl)Cl>[Cl:5][C:6]1[C:11]([NH:4][CH2:3][CH2:1][OH:2])=[C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH:9]=[CH:8][C:7]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(F)cc2)c(F)c1Cl)C(F)(F)F
Reactant: NCCO
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(F)cc2)c(NCCO)c1Cl)C(F)(F)F
Temperature: 120 °C
Yield: 33.9 %

Procedure:
Ethanolamine (47 mg, 2.5 eq) was added to a solution of (R)-N-(2-chloro-3-fluoro-4-{4-fluorophenylsulphonyl}phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 11) (135 mg) in NMP (1 ml) and the mixture was stirred and heated (oil bath 120° C.) under argon for 24 hours. The reaction mixture was cooled and partitioned between a saturated aqueous solution of ammonium chloride (10 ml) and ether (3×20 ml). The combined ether extracts were washed with water (50 ml), dried and concentrated to give a gum. The residue was dissolved in MeOH/DCM and loaded onto deactivated silica (1 g). It was then concentrated to give a free flowing powder which was poured onto an ISOLUTE column (10 g silica) and chromatographed eluting with EtOAc/isohexane to give the title compound (50 mg) as a gum. NMR: 1.65 (s, 3H), 3.2 (m, 2H), 3.42 (m, 2H), 4.92 (t, 1H), 5.91 (t, 1H), 7.47 (t, 2H), 7.89 (d, 1H), 7.96-8.08 (m, 3H), 9.85 (brs, 1H); m/z: 483.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7]CC)=[O:6].[OH-].[Na+].O.Cl>O1CCOCC1>[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:13][CH:14]=1)\[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 12 h
Yield: 96.6 %

Procedure:
Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate hydrochloride (5 g) as a suspension in dioxane (50ml) was treated at room temperature with 1M aqueous sodium hydroxide (23 ml). After stirring for 12 h, water (50 ml) was added. The pH was adjusted to 1-2 with dilute hydrochloric acid. The resulting precipitate was filtered off, washed with water and dried over P2O5 to give the title compound (4.2 g) as a white solid; δH ((CD3)2SO) 6.73 (1H, s), 7.30 (15H, s).