Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C(O)C>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: Cc1ccccc1S
Agent: [Na]
Solvent: CCO
Product: CCOC(CSc1ccccc1C)OCC
Yield: 89 %

Procedure:
In ethanol (50 mL) was dissolved sodium metal (1.6 g, 66 mmol) at 23° C. 2-Methylbenzenethiol (8.1 mL, 68 mmol) was slowly added to this solution, followed by bromoacetaldehyde diethylacetal (9.50 mL, 63 mmol). The reaction mixture was stirred at reflux for 18 h. The solvent was then evaporated in vacuo and the residue was washed with H2O (100 mL) and extracted with ether (100 mL). The organic solution was dried (MgSO4), concentrated in vacuo and purified by distillation to afford the title compound (13.48 g, 82% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.33 (1H, d, J=7.9 Hz), 7.16-7.08 (3H, m), 4.65 (1H, t, J=5.6 Hz), 3.66 (2H, q, J=7.0 Hz), 3.55 (2H, q, J=7.0 Hz), 3.09 (2H, d, J=5.6 Hz), 2.38 (3H, s), 1.20 (6H, t, J=7.0 Hz). LCMS (M+H)+ m/z 241 (t=2.65min.).
Reaction SMILES: [F:1][CH:2]1[CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[C@H:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>CO.[C].[Pd]>[F:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(F)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CC(F)CN1
Yield: 96.2 %

Procedure:
1.25 g of the compound obtained in step 5-3 and 250 mg of 10% palladium-carbon were stirred for 1 hour at room temperature and under a hydrogen atmosphere in 12.5 mL of methanol. The insolubles were filtered off and the filtrate was concentrated under reduced pressure to obtain 704 mg of the titled compound (colorless oily substance).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:15]O)([CH2:13]O)[CH2:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:9])=[CH:18][CH:19]=3)(=[O:25])=[O:24])([CH2:13][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC(CO)(CO)C2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC2(CS(=O)(=O)c3ccc(C)cc3)CC(c3ccc(F)cc3)=C(c3ccc(S(C)(=O)=O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 138.8 %

Procedure:
Under nitrogen, a solution of 2.34 mmol of the crude 1-[2-(4-fluorophenyl)-4,4-di(hydroxymethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 9) in 8 mL of pyridine at ambient temperature was treated with 1.2 g (6.3 mmol) of p-toluenesulfonyl chloride (tosyl chloride). The resulting solution was stirred at room temperature for 17 hours, concentrated in vacuo, and chromatographed on silica gel to give 1.06 g (66% overall yield from Step 9) of 1-[2-(4-fluorophenyl)-4,4-di(tosylmethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene as a colorless solid: NMR (CDCl3) δ 2.46 (s, 6H), 2.73 (s, 3H), 3.04 (s, 3H), 4.05 (s, 4H), 6.85-7.0 (m, 4H), 7.20 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 4H), 7.75 (d, J=8 Hz, 6H).
Reaction SMILES: ClCCl.[CH3:4][O:5][CH:6]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][OH:8].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([O:8][CH2:7][CH:6]([O:5][CH3:4])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OC
Yield: 99.9 %

Procedure:
To 120 ml of dichloromethane are added 12.0 g of 2-methoxy-3-octadecyloxypropanol and 6.07 ml of triethylamine, to which 4.98 g of methanesulfonyl chloride is added dropwise with stirring under ice cooling. Thereafter, the mixture is stirred at room temperature for 2 hours to complete the reaction. The reaction mixture is then washed with water, an aqueous sodium bicarbonate solution and again water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to leave 14.6 g (100%) of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(c1cccc(Br)c1)N1CCCCC1

Procedure:
Identical procedure to Step A of Example 1, starting from 3-bromobenzenesulphonyl chloride and piperidine.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>O>[O:20]=[C:14]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Oc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Phenol (1.88 g, 20.0 mmol) was dissolved in a solution of sodium carbonate (anhydrous) (1.06 g, 10.0 mmol) in water (20 ml) and cooled to 0° C. Succinic anhydride (2.00 g, 20.0 mmol) was added and the suspension was allowed to stir at 0° C. for 1 h. The reaction mixture was gradually warmed to room temperature and stirred over night. The clear solution was cooled to 0° C. and acidified to pH 0 (addition of 1M aqueous HCl). The reaction mixture was extracted with chloroform (3×25 ml), dried over Na2SO4, filtered and the solvent removed under reduced pressure to obtain a white solid (1.63 g, 8.4 mmol, 42%). The product was used without any further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:11][CH2:10]1>C(=S)=S>[C:19]1([C:5](=[O:7])[CH3:6])[C:20]2=[C:21]3[CH:12]([CH2:11][CH2:10][CH2:9]2)[CH2:13][CH2:14][CH2:15][C:16]3=[CH:17][CH:18]=1
Reactant: CC(=O)Cl
Reactant: c1cc2c3c(c1)CCCC3CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c3c1CCCC3CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
A suspension of aluminum chloride (0.250 g) in carbon disulfide (3 ml) was added with acetyl chloride (0.16 ml). The mixture was stirred at room temperature for 5 minutes, and then slowly added with 2,3,3a,4,5,6-hexahydro-1H-phenalene (0.250 g) dissolved in carbon disulfide (2 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour, and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:500) to obtain 1-(5,6,6a,7,8,9-hexahydro-4H-1-phenalenyl)ethanone (0.139 g, yield: 45%) and the title compound (0.135 g, yield: 43%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[CH2:15]([O:17][C:18]([C:20]1[N:21]([CH3:27])[C:22](Br)=[N:23][C:24]=1[CH3:25])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[N:21]([CH3:27])[C:22]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:23][C:24]=1[CH3:25])=[O:19])[CH3:16]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2c(-c3ccccc3)noc2C)n1C
Yield: 63 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 110 mg, 63%) which was obtained as a light yellow solid. MS: m/e=350.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]=3[CH:37]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:19]=3[CH:37]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]/[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.Cl>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]/[CH2:15][NH2:16]
Reactant: COc1ccc(F)c(/C=C/CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(F)c(/C=C/CN)c1
Temperature: 0 °C

Procedure:
Hydrazine hydrate (88%)(358 mg, 6.3 mmol) was slowly added to a stirring solution of trans - 2-[3-(2-fluoro-5-methoxyphenyl)prop-2-en-1-yl]-isoindole-1,3-dione (650 mg, 2.1 mmol) in EtOH (40 mL) and the solution was heated to reflux for 5h. The resulting mixture was made acidic (pH<2.0) (10N HCl) followed by heating on a steam bath for 60 min. Cooling of the suspension to 0° C. precipitated the hydrazide which was filtered off, the filtrate was then diluted with H2O (20 mL) and extracted with EtOAc(2×). The aqueous layer was made basic (50% NaOH), and extracted with Et2O (3×). The ethereal layers were combined, washed with brine, dried over MgSO4, and concentrated to give a crude white wax. Purification by Kugelrohr distillation afforded the titled compound as a clear oil, 380 mg, quantitative: 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 2H, br), 3.43 (m, 2H), 3.71 (s, 3H), 5.75 (m, 1H), 6.28 (d, J=11.4 Hz, 1H), 6.65 (m, 2H), 6.90 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[H][H]>[Pd].CO>[NH2:13][C:12]1[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cccc([N+](=O)[O-])c1NCCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#Cc1cccc(N)c1NCCO
Yield: 106.3 %

Procedure:
Methanol (500 ml) and Pd/activated charcoal 5% (wet, 3.45 g) are added to 2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile (69 g, 0.333 mol). The suspension is shaken in a Parr apparatus under 20 psi pressure of hydrogen for 1 hour. The mixture is then filtered on Celite and evaporated to dryness to give the desired material (62.7 g). This product is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([C:16]([O:18]C)=[O:17])[NH:4][C:5]([O:7][C@@H:8]1[CH2:10][C@H:9]1[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:6].O[Li].O>CO.O>[CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([C:16]([OH:18])=[O:17])[NH:4][C:5]([O:7][C@@H:8]1[CH2:10][C@H:9]1[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:6]
Reactant: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)OC)C(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 60 °C
Yield: 98 %

Procedure:
A solution (0.1 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate in 2:1 mixture of MeOH/H2O was treated with LiOH.H2O (4 eq) and then heated at 60° C. for 4 h. The mixture was cooled and concentrated to half volume, then diluted with EtOAc and acidified with aqueous HCl (1 N). The organic layer was separated and washed with brine then dried. Removal of the volatiles afforded the title compound (98%) as an oil. MS (ES+) m/z 284 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][C:14]3[N:17]=[C:18]([NH2:20])[S:19][C:13]=3[CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][C:14]3[N:17]=[C:18]([NH:20][C:30](=[O:32])[CH3:31])[S:19][C:13]=3[CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ncc(N2CCc3nc(N)sc3C2)nc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncc(N2CCc3nc(NC(C)=O)sc3C2)nc1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.2 %

Procedure:
As shown in step 9-vi of Scheme 9, to a solution of Compound 1032 (65.4 mg, 0.223 mmol) in DCM (2 mL) was added DIEA (200 μL, 1.148 mmol) and acetic anhydride (200 μL, 2.12 mmol). The reaction solution was stirred at room temperature for 150 min and the crude produce purified by medium pressure silica gel chromatography (10 to 80% EtOAc in Hexanes) to give N-(4,5,6,7-tetrahydro-5-(5,6-dimethoxypyrazin-2-yl)thiazolo[5,4-c]pyridin-2-yl)acetamide (Compound 14, 36.8 mg) as an off white solid, which was salted as its mono-mesylate salt to yield a beige solid: ESMS (M+H) 336.12; 1H NMR (300.0 MHz, DMSO-d6) δ 7.31 (s, 1H), 4.55 (s, 2H), 3.91 (m, 3H), 3.83 (m, 5H), 2.73 (t, J=5.4 Hz, 2H), 2.39 (d, J=0.6 Hz, 3H) and 2.12 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1>C(NCC)C.CC(=O)OCC>[Cl:9][C:4]1[N:3]=[C:2]([N:3]([CH2:4][CH3:5])[CH2:2][CH3:7])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CCN(CC)c1cc(C)cc(Cl)n1
Yield: 104.3 %

Procedure:
In a sealed vial, a solution of 2,6-dichloro-4-picoline (1.80 g, 11.1 mmol) in diethylamine (5 mL) is heated to 135° C. for 40 h in a microwave oven. The pressure in the vial reaches 6.5 bar. The mixture is diluted with EA (200 mL) and washed with 1 N KHSO4, solution. The washings are extracted back with EA (100 mL) and the combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 95:5 to give (6-chloro-4-methyl-pyridin-2-yl)-diethyl-amine (1.15 g) as a colourless solid; LC-MS: tR=1.05 min, [M+1]+=198.97.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([C:34](C)(C)[O:35][SiH2]C(C)(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][OH:35])[C@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:16])[CH3:17])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc1OCCCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)cc1OCCCOC

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (13.1 g, 21.6 mmol) and TBAF (17 g, 54 mmol), and purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5) to give the title compound as yellow oil. TLC, Rf (AcOEt)=0.4,MS (LC-MS): 437.3 [M+H-tBu]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.74 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:19][C:15]1[N:14]=[C:13]([NH:12][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(N)n1
Reactant: Clc1nccc2cccnc12
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nccc3cccnc23)n1
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
8-Chloro-[1,7]naphthyridine (Example A) (0.2 g, 1.2 mmol) and 2-amino-6-methylpyridine (0.13 g, 1.2 mmol) were dissolved in 8 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (145 mg, 0.24 mmol), cesium carbonate (0.63 g, 1.95 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (0.13 g, 0.12 mmol) were added and the reaction mixture was stirred under microwave irradiation for 50 minutes at 150° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 95:5->70:30 gradient). The desired product was obtained as a light yellow solid (98 mg, 34%),
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C([BH3-])#N.[Na+]>>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CCCNCCC
Reactant: O=C1CCc2cccc(Br)c2C1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCN(CCC)C1CCc2cccc(Br)c2C1

Procedure:
8-Bromo-2-tetralone (28.8 gm, 128 mMol) was reacted with dipropylamine (34.3 mL, 250 mMol) and sodium cyanoborohydride (6.3 gm, 100 mMol) as described in Example 3 to give the title compound as a light yellow oil. The hydrochloride salt was formed and crystallization (acetone) gave colorless crystals (m.p.=150.5°-152° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][C:14]([CH2:17][OH:18])([CH3:16])[C:13](=[O:19])[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:20]1[CH:25]=[C:24]2[C:26]([O:28][S:29](=[O:31])(=[O:30])[C:23]2=[CH:22][CH:21]=1)=[O:27]>O1CCCC1>[S:29]([C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][C:24]=1[C:26]([O:18][CH2:17][C:14]1([CH3:16])[CH2:15][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:12][C:13]1=[O:19])=[O:27])([OH:31])(=[O:30])=[O:28]
Reactant: O=C1OS(=O)(=O)c2ccccc21
Reactant: COc1ccc(N2CC(C)(CO)C(=O)N2)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(N2CC(C)(COC(=O)c3ccccc3S(=O)(=O)O)C(=O)N2)cc1OC
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a suspension of {1-(3,4-dimethoxyphenyl)-4-hydroxymethyl-4-methyl-3-pyrazolidinone (1.0 g, 3.76 mmol) in dry tetrahydrofuran (20 ml) was added 2-sulfobenzoic acid cyclic anhydride (0.69 g, 3.76 mmol), in a single portion at room temperature with stirring. The reaction medium was heated to reflux under nitrogen for 24 hours until complete dissolution was observed. The mixture was cooled in a ice/water bath and the solid was recovered by filtration and washed with acetonitrile. After drying under vacuum, 0.93 g (55%) of {1-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-pyrazolidin-4-yl}methyl 2-sulfobenzoate (Compound IV) was isolated in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][N:20]=[N:19]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[N:20][CH:21]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnnn2C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-5-iodo-benzoic acid methyl ester (1 g, 2.90 mmol) in dioxane (20 mL) were added 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (2.02 g, 4.34 mmol) and Pd(dppf)2Cl2 (237 mg, 0.29 mmol) and the resulting mixture was stirred at 100° C. for 24 h. A portion of catalyst (0.1 equiv) was added and the mixture was stirred at 100° C. for an additional 7 h. The solvent was removed in vacuo to afford a dark oil. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes (0:1000 to 40:60)) to provide the title compound as an off-white solid (357 mg, 41% yield). ES-MS: m/z 301.2 [M+H]+, rt 4.49 min.
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8]CC)=O)[CH2:3][CH2:2]1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:11])[CH2:5][C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)C1CC1
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C1CC1)Nc1ccc(C(F)(F)F)cc1
Yield: 93.2 %

Procedure:
A mixture of 10.14 g (65 mmol) of ethyl 3-cyclopropyl-3-oxopropanoate and 10.47 g (65 mmol) of 4-aminobenzotrifluoride in 100 ml of dry toluene was refluxed for 8 hours using a Dean-Stark condenser to remove the ethanol formed during the reaction. The reaction mixture was cooled and petroleum ether (b.p. 40°-60° C.) was added to obtain 16.44 g (93%) of 3-cyclopropyl-3-oxo-N-[4-(trifluoromethyl)phenyl]-propanamide as a white crystalline solid, melting at 131°-2° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Br:18])=[CH:20][C:21]=1[F:26])(=[O:3])[CH3:2]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: Nc1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) were added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 4-bromo-2-fluoroaniline (0.891 g, 4.69 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.42 g, 82%).