Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([Mg]Br)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH3:4])[CH:7]=2)[OH:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COc1ccc([Mg]Br)cc1OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately 3 mL of a solution of 3,4-bromoveratrole (3.5 g, 15.9 mmol) in THF (10 mL) was added to a mixture of magnesium turnings (0.4 g, 15.9 mmol) in THF (5 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining 3,4-bromoveratrole solution was added dropwise to the solution under mild reflux. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3,4-dimethoxyphenyl)magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (2.4 g, 13.3 mmol) in THF (10 mL) at 0° C. After complete addition, the solution was allowed to stir at room temperature for 1 h. The mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (40 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed and residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to give (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol as an oil (2.6 g, 63%): 1H NMR (CDCl3) δ 7.89 (d, J=2 Hz, 1H), 7.54-7.49 (dd, J=2, 8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.88-6.81 (m, 3H), 5.78 (d, J=3 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 2.38 (d, J=3 Hz, 1H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].[BH3-]C#N.[Na+].C(O)(C(F)(F)F)=O>CO>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:16][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC/C=C/CCC=O
Reactant: COC(CN)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCC/C=C/CCCNCC(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-4-Decenal (7.2 g, 46.6 mmol) was mixed with 40 mL (0.37 moL) of aminoacetaldehyde dimethylacetal in 400 mL of methanol and stirred at room temperature for 30 minutes. NaCNBH3 (2.9 g, 46.6 mmol) was added, the reaction was cooled in an ice bath, and 27 mL (0.35 moL) of TFA was added dropwise over 5 minutes. The ice bath was then removed and the reaction was stirred for 70 minutes at room temperature, concentrated to a third of its volume, and partitioned between ethyl acetate (250 mL) and 1N NaOH (200 mL). The organic layer was washed with water (3×75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield 11.1 g (45.6 mmol) of 2-(trans-dec-4-en-1-ylamino)acetaldehyde dimethyl acetal as a yellow oil that was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].[ClH:28]>C1COCC1.CO>[ClH:28].[F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ncccc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
24.06 g (70.1 mmol) of ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 120A were initially charged in 1.5 l of THF/methanol (5:1), 350.4 ml (350.4 mmol) of 1 N aqueous lithium hydroxide solution were added and the reaction mixture was stirred at 40° C. for 2.5 h. After cooling, the pH was adjusted to about 4 using 1 N aqueous hydrochloric acid and the solution was freed from THF/methanol under reduced pressure. The residue was cooled and the precipitated solid was filtered off and dried under reduced pressure. This gave 22.27 g (100% of theory) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:13]=1
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccc2F)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 2-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.94 (td, J=19.93, 6.60 Hz, 6H), 1.58 (dt, J=13.39, 6.63 Hz, 1H), 1.78 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 2.01-2.11 (m, 1H), 3.80 (t, J=7.83 Hz, 1H), 7.16-7.27 (m, 2H), 7.29-7.40 (m, 1H), 7.47 (td, J=7.70, 1.71 Hz, 1H), 7.52-7.61 (m, 2H), 7.66-7.76 (m, 5H); Calcd for C25H22F4O2 (M+Na) 453.16, Found 453.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=O)=[CH:18][CH:19]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: COc1ccc(C=O)cc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(C=Cc2ccc(OC)cc2)nc1

Procedure:
The starting material was prepared by refluxing for 72 hours a mixture of methyl 6-methylnicotinate (60.4 g.), anisaldehyde (163.3 g.), acetic anhydride (120 ml.) and xylene (320 ml.). Steam distillation was used to remove the excess anisaldehyde, the acetic acid formed during the reaction and xylene. The residue was dried in the cold, washed with ether, and dried at 60° C. for 12 hours to give methyl 6-p-methoxystyrylnicotinate, m.p. 170° C.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Add triethylamine (1.93 mL, 13.64 mmol), copper (I) iodide (37.3 mg, 0.190 mmol) and bis(triphenylphosphine)palladium (II) dichloride (120 mg, 0.170 mmol) to a solution of 5-bromonicotinonitrile (624 mg, 3.41 mmol) and 1-ethynyl-3-trifluoromethylbenzene, (prepared essentially as described in PREPARATION 13), (580 mg, 3.41 mmol) in ethyl acetate (3 mL). Stir in a sealed tube at 50° C. for 18 h, concentrate and purify by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate to give the title compound (400 mg, 43%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=2)=[C:16]([CH:20]=1)[C:17]([O:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1)=[O:18]
Reactant: Fc1ccc(CBr)cc1F
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)c(F)c1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Neat 4-(bromomethyl)-1,2-difluorobenzene (1526 mg, 7.37 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmol) in acetone (60 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After filtering, the filtrate was evaporated to give a solid, which was dried in vacuo to yield the title compound as a white solid. 2.0 g.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][CH2:15][C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([OH:20])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:29](I)[CH3:30]>O.CO>[CH2:7]([O:14][CH2:15][C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([O:20][CH2:29][CH3:30])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of cesium carbonate (3.53 g, 10.9 mmol) in water (22 ml) was added to an ice-cooled solution of (3S)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]butanoic acid (3.36 g, 10.9 mmol) in methanol (70 ml) and water (7 ml), and the reaction stirred for 20 minutes. The mixture was concentrated under reduced pressure and azeotroped with N,N-dimethylformamide and dichloromethane. The residual oil was dissolved in N,N-dimethylformamide (70 ml), ethyl iodide (1.64 g, 10.9 mmol) added, and the reaction stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, suspended in ethyl acetate (300 ml), washed with water (4×), brine, then dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using hexane:ethyl acetate (85:15) to afford the title compound as a pale yellow oil, 2.86 g; 1H NMR (CDCl3, 400 MHz) δ: 1.26 (t, 3H), 1.45 (s, 9H), 2.65 (d, 2H), 3.58 (m, 2H), 4.17 (m, 3H), 4.55 (s, 2H), 5.20 (bs, 1H), 7.36 (m, 5H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:13][N:14]([O:15][CH3:16])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nc[nH]c2c1
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To a suspension of 5-benzimidazolecarboxylic acid (1.62 g, 10 mmol) in CH2Cl2 (30 mL) was added N,O-dimethylhydroxylamine (1.17 g, 12 mmol), N-methylmorpholine (1.65 mL, 15 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g, 12 mmol), respectively at room temperature. After stirring for 24 h, the reaction mixture was filtered to remove solid and rinsed thoroughly with CH2Cl2. The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 5% MeOH/CH2Cl2 as an eluent to obtain 890 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.02 (s, 2H); 7.59 (d, J=7.6 Hz, 2H); 3.58 (s, 3H); 3.4 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]([CH3:20])[CH3:19])[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:18]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])=[CH:15][CH:16]=2)=[CH:9]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1cc(-c2ccc(O)cc2)c2c(N)ncnc21
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccc(Oc3ccccc3[N+](=O)[O-])cc2)c2c(N)ncnc21
Temperature: 120 °C

Procedure:
A mixture of 4-amino-5-(4-hydroxyphenyl)-7-isopropylpyrrolo[2,3-d]-pyrimidine (0.29 g), 2-fluoronitrobenzene (0.15 g), potassium carbonate (0.149 g) and N,N-dimethylformamide (4.0 ml) was shaken and heated at 120° C. for 5 hours. The mixture was evaporated to dryness under reduced pressure and the residue was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with water, and then with dilute sodium hydroxide solution, and then with brine, then dried, filtered and evaporated to give a solid which was triturated with ether to give 7-isopropyl-5-[4-(2-nitrophenoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. The structure was confirmed by 1H nmr.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9](OC)=[O:10])[CH:6]=[C:5]([CH3:13])[N:4]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:13])[N:4]=1
Reactant: COC(=O)c1cc(C)nc(OC)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(C)cc(C=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 0.5 g of methyl 2-methoxy-6-methylpyrimidine-4-carboxylate in 15 mL of toluene and 15 mL of dichloromethane was added 6 mL of 1 M diisobutyl aluminum hydride in toluene. After stirring 10 min the reaction was quenched with 5 mL of water, allowed to warm to room temperature and dried with 5 g of MgSO4. Concentration of the filtrate under reduced pressure gave the product as an resin and was used without further purification: MS (m+1)=153.1 and 171.1 (hydrate).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CCCCO>[CH:21]1([NH:27][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1nc(Nc2ccc(N3CCOCC3)cc2)cc(NC2CCCCC2)n1
Temperature: 200 °C
Yield: 44 %

Procedure:
78 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 55 mg of cyclohexylamine and 72 mg if DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 90 minutes under microwave irradiation. Upon evaporation of n-BuOH a precipitate formed and was subjected to crystallization from n-BuOH-EtOH solvent mixture. N4-Cyclohexyl-N6-(4-morpholinophenyl)pyrimidine-4,6-diamine was obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[C:3]1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH:18](OC)=[O:19].C(=O)=O>C1COCC1>[OH:19][CH:18]=[C:11]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1C
Reactant: COC=O
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Temperature: 118 °C
Reaction time: 0.83 h

Procedure:
To a suspension of methyl 1-methyl-2-[2-(methyloxy)-2-oxoethyl]-1H-pyrrole-3-carboxylate (37.9 g) in THF (anhydrous, 300 ml), under argon, was added sodium hydride (60% dispersion in mineral oil, 37.9 g) portion-wise. After complete addition the reaction was stirred at 22° C. for 15 minutes before the drop-wise addition of methyl formate (16.6 ml). The reaction was stirred at 118° C. for 50 minutes. During this period the temperature increased to around 21.5° C. before a rapid rise in temperature with gas evolution. Cooling (solid carbon dioxide) was applied to the outside of the flask. The temperature reached a maximum of 30° C. before dropping to 20° C. The coolant was removed and the reaction stirred for a further 17 hours. The reaction mixture was cooled by an ice/water bath before the cautious addition of methanol (100 ml). The reaction mixture was then combined with the product of another second mixture prepared in a similar manner (starting weight of methyl 1-methyl-2-[2-(methyloxy)-2-oxoethyl]-1H-pyrrole-3-carboxylate was 35.5 g). The solution was concentrated in vacuo. The residue was treated with saturated ammonium chloride solution (600 ml) then acidified to pH1 by the cautious addition concentrated hydrochloric acid. Ice was added to cool the solution and it was then extracted with ethyl acetate (3×400 ml). The combined organics were dried (MgSO4) and the solvent removed to yield a black oily solid. Oil was decanted and the residue triturated with hexane (2×200 ml), diethyl ether (200 ml) and hexane (200 ml). This yielded the title compound as a brown solid (65.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[Cl:9][C:10]1[C:11]([F:35])=[N:12][C:13](NCC(OC)=O)=[C:14]([Cl:28])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1>>[Cl:9][C:10]1[C:11]([F:35])=[N:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])=[C:14]([Cl:28])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1
Reactant: NCCCS(=O)(=O)O
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCCS(=O)(=O)O)c2Cl)ccc1O

Procedure:
By use of 3-aminopropylsulfonic acid in place of glycine methyl ester ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:33]([Si:35]([C:40]#[CH:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:34]#[C:33][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:3]=3)[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:23]=1
Reactant: C#C[Si](CC)(CC)CC
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(Br)c2)c2cccnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1cncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)c1)(CC)CC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A solution of 415 mg (1.00 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine in 5 ml DMF was flushed with nitrogen and subsequently treated with 70 mg (0.10 mmol) bis-(triphenylphosphine)-palladium(II)-chloride, 6.0 mg (0.03 mmol) cuprous iodide, 0.42 ml (3.0 mmol) triethylamine and 450 μl (2.5 mmol) triethylsilyl acetylene. The resulting slurry was stirred at 120° C. for two hours. The reaction mixture was cooled to room temperature and partitioned between ethylacetate and brine. The combined organic phases were dried with sodium sulfate and evaporated yielding 2-(5-chloro-2-fluoro-phenyl)-4-(5-triethylsilanylethynyl-pyridin-3-yl)-[1,8]naphthyridine as brown solid; HPLC-MS: 2.73 min, [M+H] 474.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([OH:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH3:11])[O:12][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 3 h
Yield: 87.3 %

Procedure:
(2R)-1-{[tert-Butyl(dimethyl)silyl]oxy}propan-2-ol (2.18 g, 11.47 mmol) was added to a solution of methyl 3-hydroxy-5-[4-(methylsulfonyl)phenoxy]benzoate (2.76 g, 8.57 mmol) in dry DCM (100 mL) followed by addition of polymer-supported triphenylphosphine (3.0 mmol/g (Fluka), 8.57 g, 25.71 mmol) and DIAD (3.37 mL, 17.1 mmol) at RT. The reaction was stirred for 3 h before filtration through diatomaceous earth and evaporation. Purification by column chromatography, eluting with 1:4 to 1:2 ethyl acetate:hexanes, afforded the title compound as a colourless oil (3.70 g, 87%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Cl[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1>CN(C=O)C>[CH3:32][C:31]1[C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=[C:29]([N+:33]([O-:35])=[O:34])[CH:30]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
To the solution of benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (3.0 g, 9.89 mmol) in 10 ml of anhydrous DMF was added NaH (0.40 g, 9.89 mmol) in small portions at RT and the final resulting solution was stirred for 15 min. Commercially available 2-chloro-3-methyl-5-nitropyridine (1.37 g, 7.91 mmol) was added in 10 portions over 2 minutes and the resulting mixture was stirred 3 hrs at RT. The reaction mixture was quenched with ice cooled aqueous sat'd NH4Cl solution and extracted with ethyl acetate/ether (1:1) (2×50 mL). The organics were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (40M+ silica gel) using a gradient eluant of 0-60% ethyl acetate in hexane (800 ml) to afford the title compound. LC/MS (m/z): 440 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])(=[O:40])=[O:39])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Reactant: COc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1S(=O)(=O)NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added 2-methoxybenzenesulfonyl chloride (0.096 mmol, 19.91 mg) and the whole stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give a white solid (13.0 mg, 0.027 mmol, 28%). [M+H]+ 482.2.