Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[CH:5][N:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:35]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:6][CH:5]=2)[CH2:10][CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:2]1=[O:1])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NC1Cc2cc(-c3ccccc3)ncc2NC1=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a solution of 3F (400 mg, 1.07 mmol) in DMF (8 mL) was added cesium carbonate (873 mg, 2.68 mmol), followed by benzyl bromide (0.38 mL, 3.21 mmol). The reaction mixture was stirred at 50° C. for 1 h. After cooling to RT, water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×30 mL). During the extraction, some precipitates formed. The solid was collected by filtration and washed with EtOAc to give the title compound (250 mg). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give additional 160 mg of the title compound (total 410 mg, 83%) as a white solid. LC/MS (method A): retention time=3.55 min, (M+H)+=464.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>C1COCC1>[CH2:38]([N:40]([CH2:41][CH3:42])[CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:33]2[C:32](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:39]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.385 g, 0.717 mmol) and diethylamine (2.0 mL, 19 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 20 minutes to give diethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine a clear amber gum (0.269 g, 85.7%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a brown foam (0.253 g); Mass Spectrum (+EI, [M+H]+) m/z 438. 1HNMR (500 MHz, DMSO-d6): δ10.11-10.12 (br, 1H), 8.74 (d, 1H, J=8.66 Hz), 8.50-8.52 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.37 (d, 1H, J=2.20 Hz), 7.21 (dd, 1H, J=9.27 Hz and 2.32 Hz), 4.41-4.43 (m, 2H), 4.05 (s, 3H), 3.49-3.52 (m, 2H), 3.15-3.25 (m, 4H), 1.22-1.25 ppm (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH2:13][CH2:14][NH:15]C(=O)OCC2C=CC=CC=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.C1CCCCC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:15][CH2:14][CH2:13][S:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:12]
Reactant: COc1ccc(NS(=O)(=O)CCNC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(NS(=O)(=O)CCN)cc1
Yield: 61.5 %

Procedure:
A solution comprised of benzyl 2-(4-methoxyphenylsulfamoyl)ethylcarbamate (2.78 g, 7.63 mmol), prepared as in Reference 1, in ethanol (20 mL) and cyclohexene (20 mL) was treated with 20% palladium hydroxide (0.95 g). The mixture was heated at reflux for 2 hours, cooled, and concentrated to dryness. The solid was triturated with ether, filtered and dried to provide 2-amino-N-(4-methoxyphenyl)ethanesulfonamide (1.08 grams, 61% yield). 1H NMR (DMSO-d6): 2.86 (2H, t, J=6.4 Hz); 3.04 (2H, t, J=6.4 Hz); 3.72 (3H, s); 4.16 (2H, br. s); 6.87 (2H, d, J=9 Hz); 7.05 (2H, d, J=9 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(=O)O[CH2:11][CH2:10][O:9]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1(=O)OCCO1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:11][CH2:10][OH:9])[CH:3]=1
Reactant: O=C1OCCO1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1cccnc1
Temperature: 86 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
3-hydroxypyridine (20.0 kg), ethylene carbonate (19.4 kg), K2CO3 (18.9 kg), and DMF (75.5 kg) were charged to a 400 L reactor and heated to 86° C. After 13H, an aliquot was taken. There was still some 3-hydroxypyridine left by GC so more ethylene carbonate (1.0 kg) was added. After 20H, the reaction was deemed complete. The reaction was cooled to 20° C., H2O (85 L) was slowly added to the 400 L reactor, and stirring continued for 30 min. The title compound was extracted with 35° C. CH2Cl2 (4×170 L) sending the CH2Cl2 extractions into the 1000 L portable tank. The aqueous layer was discarded, and the 400 L reactor was cleaned. The solution of the title compound in the 1000 L portable tank was transferred to the 400 L and distilled in the 400 L reactor sending the distillate to the 400 L receiver. Toluene (200 L) was added so the 400 L reactor and distilled sending the distillate to the 400 L receiver. The resulting oil was transferred to a 20 L glass bottle to produce 21.0 kg (72%) of the title compound of 100.0% GC purity.
Reaction SMILES: N#N.[CH2:3]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:6]=1[NH2:7])[CH3:4].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:3]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:6]=1[NH:7][CH2:16][C:15]#[CH:14])[CH3:4]
Reactant: CCc1cccc(CC)c1N
Reactant: C#CCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCNc1c(CC)cccc1CC

Procedure:
A reactor equipped with a thermometer, stirrer, N2 inlet and outlet tubes and reflux condenser fitted with a drying tube is charged with 74.5 g (0.5 mole) of 2,6-diethylaniline, 71.4 g (0.6 mole) of propargyl bromide, 41.4 g (0.3 mole) of anhydrous potassium carbonate, and 125 ml of absolute ethanol. The mixture is refluxed for 18 hours under slight positive N2 pressure. The reaction mixture is cooled and additional potassium carbonate is added until the solution is weakly basic. It is then transferred to a separatory funnel. The supernatant organic layer which develops is isolated and dried over anhydrous potassium carbonate. The liquid is then separated by filtration and the solvent stripped in vacuo. The residue remaining is vacuum distilled. The clear liquid product (17.6 g) is approximately 90% pure 2,6-diethyl-N-propargylaniline as indicated by vapor phase chromatography. It has a boiling point of 86°-88° C at 0.6-0.7 mm Hg pressure. The impurities are 2,6-diethylaniline and 2,6-diethyl-N,N-dipropargylaniline.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][N:8]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:7]2[N:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a N,N-dimethylformamide (100 mL) solution of 2-chloro-5-cyanopyridine (36.2 g, 262 mmol) and 4-hydroxypiperidine (27.9 g, 275 mmol) was added potassium carbonate (40.1 g, 290 mmol). The reaction mixture was heated to 100° C. and stirred for 3 hours. It was cooled to room temperature, diluted with water (400 mL), and extracted with dichloromethane (3×250 mL). The combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo to afford the title compound as a solid. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=2.3 Hz, 1H), 7.58 (dd, J=9.1, 2.4 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 4.10 (dt, J=13.6, 5.0 Hz, 2H), 4.01 (tt, J=8.3, 3.9 Hz, 1H), 3.37 (ddd, J=13.6, 9.2, 3.4 Hz, 2H), 2.61 (s, 1H), 1.99-1.92 (m, 2H), 1.62-1.53 (m, 2H); LC-MS: m/z 204.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1>C(Cl)(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:11]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1cccnc1
Solvent: ClC(Cl)Cl
Product: c1cncc(-c2nc3ccccc3s2)c1

Procedure:
o-Aminothiophenol 36.9 g (0.30 mole) and nicotinic acid 55.5 g (0.45 mole) are dissolved in 600 cc of chloroform and 360 g of polyphosphoric acid ethyl ester (PPE). The resulting solution is heated at reflux for 1 hour. It is then concentrated to dryness. The residue is poured onto 1500 cc of ice-water, and the resulting mixture is brought to pH 10 with 50% NaOH solution. The aqueous mixture is extracted with CHCl3, and the extracts dried (MgSO4), filtered, and concentrated in vacuo. The residue is recrystallized from acetonitrile to yield the title A compound (42.8 g, 68%, of theory).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc([N+](=O)[O-])c1)OCc1ccccc1
Yield: 100.1 %

Procedure:
To a mixture of O-benzylglycine p-toluenesulfonic acid salt (6.41 g) and triethylamine (4.04 g) in methylene chloride (100 ml) was added portionwise 3-nitrobenzoyl chloride (3.71 g) under cooling in an ice-bath and stirring. The resultant mixture was stirred for 1 hour under the same condition and for 1 hour further at ambient temperature. From the reaction mixture, methylene chloride was removed in vacuo and to the residue were added water and ethyl acetate with stirring. The separated organic layer was washed with diluted hydrochloric acid, aqueous sodium bicarbonate and water twice respectively. The extract was dried over magnesium sulfate and evaporated in vacuo to give N-(3-nitrobenzoyl)glycine benzyl ester (5.98 g). 1H-NMR (CDCl3, δ): 4.31 (2H, d, J=5.2 Hz), 5.24 (2H, s), 6.99 (1H, br, t, J=5.2 Hz), 7.38 (5H, s), 7.64 (1H, t, J=7.9 Hz), 8.15 (1H, d, t, J=7.9 Hz, 2.2 Hz), 8.35 (1H, d, t, J=7.9 Hz, 2.2 Hz), 8.64 (1H, t, J=2.2 Hz); APCI-MS (CHCl3) (m/z): 315 (M+ +1)
Reaction SMILES: N[C@@H]1CCN(C2C(Cl)=C(NC3N=[C:21]([NH:23][CH:24]4[CH2:26]C4)[C:20]4=[N:27][CH:28]=C(C#N)N4N=3)C=C(C#N)C=2)C[C@H]1O.[Cl:34][C:35]1[C:40]([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:51][CH2:50]3)[C:45]3=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:44]3[N:43]=2)=[CH:39][C:38]([C:57]#[N:58])=[CH:37][C:36]=1[N:59]1[CH2:64][CH2:63][C@@H:62]([NH:65][C:66](=O)[O:67]CCN(C)C)[C@H:61]([OH:74])[CH2:60]1>>[Cl:34][C:35]1[C:40]([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:51][CH2:50]3)[C:45]3=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:44]3[N:43]=2)=[CH:39][C:38]([C:57]#[N:58])=[CH:37][C:36]=1[N:59]1[CH2:64][CH2:63][C@@H:62]([NH:65][C:66]([N:23]2[CH2:21][CH2:20][N:27]([CH3:28])[CH2:26][CH2:24]2)=[O:67])[C@H:61]([OH:74])[CH2:60]1
Reactant: CN(C)CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CC[C@@H](N)[C@H](O)C2)c1
Product: CN1CCN(C(=O)N[C@@H]2CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)C[C@H]2O)CC1

Procedure:
The title compound was prepared from (+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (byproduct from Example 177), using a method analogous to that used to prepare Example 181.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2-:11].[Na+]>C1(C)C(C)=CC=CC=1>[NH2:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: c1cc2c(cn1)CCCC2
Reactant: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Nc1nccc2c1CCCC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
Using the method described in Example 63, Step B, a mixture of 2.0 g (15.0 mmol) of 5,6,7,8-tetrahydroisoquinoline and 644 mg (16.5 mmol) of sodium amide in 2.5 mL of xylene was stirred at 150° C. overnight. The crude material was purified by flash column chromatography on silica gel eluting with 0-100% ethyl acetate/dichloromethane, and the partially purified material was distilled using a Kugelrohr apparatus at 100-105° C. (0.3 mm). Recrystallization of the distallate from a hexane/toluene mixture gave 120 mg of 1-amino-5,6,7,8-tetrahydroisoquinoline as a white solid containing approximately 7% of 1-aminoisoquinoline.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH2:20][C:21]3[N:22]=[C:23]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=4)[O:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Nc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CNc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
4-(4-[1,2,3]Triazol-1-yl-butyl)-phenylamine (0.304 g, 1 mmol) is dissolved in anhydrous N,N-dimethylformamide (5 ml) followed by the addition of sodium hydride (0.024 g, 1 mmol). After stirring for 15 min at room temperature 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole (0.324 g, 1.5 mmol) is added and the mixture stirred for 16 h at 80° C. Ethyl acetate (25 ml) is added, the mixture is washed with brine, dried over sodium sulfate and concentrated in vacuo. After flash column chromatography (ethyl acetate/hexanes 1:1->2:1) [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethyl}-amine 1 can be isolated as a yellow solid. Yield 0.14 g (29%); m.p. 103–105° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:15][C:16]1[N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:20](=[O:27])[C:19]([N+:28]([O-:30])=[O:29])=[C:18](OS(C(F)(F)F)(=O)=O)[CH:17]=1.Cl>O1CCCC1>[CH3:15][C:16]1[N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:20](=[O:27])[C:19]([N+:28]([O-:30])=[O:29])=[C:18]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: Sc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(C)cc(Sc2ccccc2)c([N+](=O)[O-])c1=O
Reaction time: 0.08 h

Procedure:
1.5 ml (14.6 mmol) of thiophenol are placed in 20 ml of tetrahydrofuran and 2.1 ml (15.1 mmol) of triethylamine are added. 5.24 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4- [[(trifluoromethyl)sulphonyl]-oxy]-1,2-dihydropyridine-1-acetate are added dropwise at room temperature, the mixture is left for 5 minutes at room temperature and then it is poured over 20 ml of a 1 N aqueous hydrochloric acid solution. The reaction medium is extracted with twice 20 ml of dichloromethane, washed with 20 ml of a saturated sodium chloride solution and dried over magnesium sulphate and evaporated to dryness. The residue is washed with ether and it is dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:14][CH2:15]O>Cl>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-4-methoxyphenylacetic acid (4.1 g, 16.7 mmol) and concentrated hydrogen chloride (2 drops) in EtOH (100 mL) were stirred at 80° C. for 3 days. After cooling to room temperature, the mixture was concentrated to dryness to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[O:4].C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.[H][H]>C1(C)C=CC=CC=1>[C:3]([O:2][CH3:1])(=[O:4])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: [H][H]
Reactant: COC(=O)C(=O)c1ccccc1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](O)c1ccccc1
Yield: 75.2 %

Procedure:
The cross-linked Ir—Pt cluster composition obtained in Example 11 (10.0 mg), methyl benzoyl formate (164.2 mg, 1.0 mmole), (−) cinchonidine (3.8 mg, 0.013 mmole) and toluene (5 ml) were mixed in an autoclave and agitated for five hours at room temperature in a hydrogen atmosphere at a pressure of 50 atmospheres. The cross linked Ir—Pt cluster composition was removed by filtration after the reaction. The filtrate was concentrated, and the residue was purified using PTLC to obtain (R)-methyl mandelate (125 mg, 75% yield). The asymmetric yield was 52% ee.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1>[Ni].CCO>[NH2:11][C:10]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: NC(=O)c1cnc(N)c(N)c1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A mixture of 65 (168 mg, 0.92 mmol), Raney Ni (about 200 mg) and EtOH (25 mL) was shaken under H2 (40 psi) for 1 h, then filtered. The filtrate was evaporated to give 121 mg (86%) of the diamine 66 as a gray powder, mp 227°-9° C.(dec.). 1H NMR (DMSO-d6), 4.747 (s, 2H), 5.890 (s, 2H), 6.867 (bs, 1H), 7.102 (s, 1H), 7.530 (bs, 1H), 7.861 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:31][C:32]([C@@H:34](OS(C(F)(F)F)(=O)=O)[CH3:35])=[O:33]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][N:20]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C@@H:34]([C:32]([OH:33])=[O:31])[CH3:35])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COC[C@H](C)NCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Product: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-({[(1S)-2-methoxy-1-methylethyl]amino}methyl)quinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[(1S)-2-methoxy-1-methylethyl]-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 3H); 1.32 (d, 3H); 3.04 (m, 1H); 3.14 (s, 3H); 3.22 (dd, 1H); 3.43 (dd, 1H); 3.69 (q, 1H); 3.96 (m, 4H); 4.05 (d, 1H); 7.19 (s, 1H); 7.29 (t, 1H); 7.49 (t, 1H); 7.60 (t, 1H); 8.43 (m, 2H); 9.64 (brs, 1H); 12.01 (brs, 1H); Mass Spectrum: (M+H)+ 477.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(Cl)cc1C
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-N-methoxy-N-methylpropanamide (example 138, step 3) to give the title compound as a light yellow oil, MS (ESI+): m/z=446.03 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M60) (0.33 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (206 mg, 81%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=[O:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Li+]>CO>[C:29]([CH2:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1)=[O:32])([OH:31])=[O:30]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (89 mg, 0.19 mmol) in 5 ml of methanol was added lithium hydroxide solution (0.5 N, 1.0 ml). The mixture was stirred at room temperature overnight. The reaction mixture was loaded to a preparative HPLC for purification to give 1-(3-Carboxymethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid as a fluffy solid (72.6 mg, 92%). ES-MS calcd for C21H17NO8 (m/e) 411.4, obsd 412.3 (M+H).