Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C(COC)OC.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:21]3[CH:22]=[CH:23][C:18]([CH:16]=[O:17])=[CH:19][CH:20]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(C=O)cc3)n2n1
Temperature: 160 °C
Yield: 71.6 %

Procedure:
To a mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (100 mg, 0.37 mmol), (4-formylphenyl)boronic acid (139 mg, 0.93 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.5 mg, 0.02 mmol) and potassium phosphate (236 mg, 1.11 mmol) was added 3:1 dimethoxyethane/water (2 mL). The resulting mixture was heated at 160° C. (microwave) for 6 min. After the reaction was cooled down and separated into two layers, the dark upper layer was then filtered and diluted with a mixture of 1:1:1 methanol/water/acetonitrile, and then filtered again. The filtration was finally purified by preparative HPLC (neutral) to afford 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzaldehyde (78 mg, 72% yield) as a yellow solid: 1H NMR (METHANOL-d4) δ: 10.01 (s, 1H), 8.47 (d, J=8.6 Hz, 2H), 7.98-8.03 (m, 2H), 7.97 (s, 1H), 7.66 (d, J=9.6 Hz, 1H), 6.77 (d, J=9.6 Hz, 1H), 3.42 (t, J=7.1 Hz, 2H), 1.74 (t, J=7.2 Hz, 2H), 1.52 (d, J=7.8 Hz, 2H), 1.03 (t, J=7.5 Hz, 4H); LRMS (ESI) m/e 295.2 [(M+H)+, calcd for C17H19N4O 295.2].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>ClC(Cl)(Cl)C(O)=O.C1(C)C=CC=CC=1>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 g of trichloroacetic acid and 5 ml of toluene is heated to 110° C. The mixture is maintained and stirred at this temperature for 3 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water and ethyl acetate. After drying, 0.6 g of raw deferasirox is obtained, i.e. 55% of the theory, with an HPLC content of 99.56% and a melting temperature of 258 to 262° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[N:38][CH:37]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccnnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 40.2 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), 4-tributylstannanyl-pyridazine (83 mg, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (10-100% EtOAc/hexanes+1% AcOH) to give 28 mg of the title compound. MS: (+) m/z 465.42 (M+1).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:18]>O.[Cu]Br>[Br:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Suspend 2-amino-6-nitrobenzthiazole (20.0 g, 102 mmol) and copper (I) bromide (1.75 g, 12.2 mmol) in 18% HBr (aqueous) (200 mL) and water (180 mL). Slowly add sodium nitrite (61.0 g, 884 mmol). Continue to stir at room temperature for 30 min. Filter and dry on the filter flask overnight, to afford the title compound (24.6 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (d, 1H, J=2.2 Hz), 8.36 (dd, 1H, J=9.0, 2.4 Hz), 8.20 (d, 1H, J=9.2 Hz).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]([NH:15][C@H:16]2[C@H:19]([CH3:20])[N:18]([O:21]CC3C=CC=CC=3)[C:17]2=[O:29])=[O:14])=[O:10])[C:5](=[O:36])[C:4]1=[O:37])[CH3:2]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:13]([NH:15][C@H:16]2[C@H:19]([CH3:20])[N:18]([OH:21])[C:17]2=[O:29])=[O:14])=[O:10])[C:5](=[O:36])[C:4]1=[O:37])[CH3:2]
Reactant: CCN1CCN(C(=O)NC(C(=O)N[C@@H]2C(=O)N(OCc3ccccc3)[C@H]2C)c2ccccc2)C(=O)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCN1CCN(C(=O)NC(C(=O)N[C@@H]2C(=O)N(O)[C@H]2C)c2ccccc2)C(=O)C1=O

Procedure:
(3S-trans)-3-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]-4-methyl-1-(phenylmethoxy)-2-azetidinone (0.270 g) is dissolved in ethanol (25 ml) and hydrogenated over 10% palladium on charcoal catalyst (130 mg) for two hours. The reaction mixture is filtered and concentrated to a solid (0.220 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:10])([C:8]#[CH:9])[CH3:7].[H-].[Na+].[CH3:13]I>CN(C=O)C>[CH3:13][O:10][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([C:8]#[CH:9])[CH3:7]
Reactant: CI
Reactant: C#CC(C)(O)c1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(OC)c1nccs1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (1.0 g, 6.33 mmol) in DMF (15 mL) cooled to 0° C., was slowly added sodium hydride (60% oil dispersion) (0.30 g, 7.6 mmol). After stirring at 0° C. for 20 min, methyl iodide (0.47 mL, 7.6 mmol) was added. The solution was warmed to RT. The mixture was partition between EtOAc (50 mL) and water (20 mL). The organic layer was washed with water, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (Isolute column, 20% EtOAc in heptane) gave the title compound as a pale yellow oil: 1H NMR (250 MHz, CDCl3) δ 1.91 (3H, s), 2.78 (1H, s), 3.41 (3H, s), 7.35 (1H, d, J=3.20 Hz), 7.80 (1H, d, J=3.20 Hz); LC-MS: m/z=+167.9 (M+H)+.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Si:15]([O:32][C@H:33]([CH3:53])[C@H:34]([N:44]1[CH2:49][C@H:48]([CH3:50])[O:47][C:46](=[O:51])[C:45]1=[O:52])[C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].OO.S(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O>[Si:15]([O:32][C@H:33]([CH3:53])[C@H:34]([N:44]1[CH2:49][CH:48]([CH3:50])[O:47][C@H:46]([OH:51])[C:45]1=[O:52])[C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)([C:28]([CH3:29])([CH3:31])[CH3:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H]1CN([C@H](c2cc(F)c(F)c(F)c2)[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)C(=O)O1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=S([O-])O
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: CC1CN([C@H](c2cc(F)c(F)c(F)c2)[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)[C@@H](O)O1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A solution of lithium tri-sec-butylborohydride (1.06 mol) in THF (0.25 ml) was added dropwise to a solution of (S)-4-[(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propyl]-6-methylmorpholine-2,3-dione (95 mg) in THF (3 ml) in a nitrogen atmosphere at −20° C., and the reaction solution was stirred at the same temperature for 30 minutes. A 5 N sodium hydroxide solution (0.03 ml) and 30% aqueous hydrogen peroxide (0.07 ml) were added to the reaction solution, which was then stirred under ice-cooling for one hour. Thereafter, Sodium bisulfite powder (20 mg) was added, and the reaction solution was stirred at room temperature for 30 minutes. Brine was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain 93 mg of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9][C:8]1=O>C1COCC1>[NH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9][CH2:8]1
Reactant: O=C1CNc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCN2
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a solution of lithium aluminum hydride (28.2 g, 742 mmol) in THF (1500 mL) at 0° C. was added 3,4-dihydroquinoxalin-2(1H)-one (50 g, 337 mmol) portion wise. The reaction mixture was warmed up to room temperature and heated at 80° C. for 4 h. The reaction mixture was cooled to 0° C. and quenched with water (20 mL) dropwise. The insoluble inorganics was filtered through CELITE®. The filtrate was dried over Na2SO4, filtered, concentrated to afford 1,2,3,4-tetrahydroquinoxaline (36 g, 268 mmol, 80% yield). NMR: 1H NMR (400 MHz, CDCl3) δ ppm 6.6 (2H, m), 6.5 (2H, m), 3.65 (2H, bs), 3.40 (4H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O.Cl>C(O)(=O)C>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(F)cc3)cnc21
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccc(F)cc4)c3cnc21
Yield: 52.6 %

Procedure:
4-Chloro-1-ethyl-5-(4-fluorobenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.5 g) and hydroxylamine hydrochloride (14.0 g) were refluxed in a solution of 250 ml of acetic acid and 4 ml of concentrated hydrochloric acid. After two hours the solvent was evaporated and the residue distributed between dichloromethane and an aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). Evaporation of the appropriate fractions gave 2.2 g of product after trituration with pentane, mp 222°-223° C.
Reaction SMILES: ClS([C:5]1[C:6]([Cl:15])=[C:7]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(N)CCC>C1(C)C=CC=CC=1.Cl>[Cl:14][C:11]1[CH:12]=[CH:13][CH:5]=[C:6]([Cl:15])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCN
Product: O=C(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Part B: 3-(Chlorosulfonyl)-2,6-dichlorobenzoic acid (1.5 g; 5.2 mmol) was dissolved in anhydrous toluene (35 ml) to which was added powdered K2CO3 (1.44 g: 10.4 mmol) and n-butylamine (1.0 ml, 10.4 mmol). The reaction mixture was stirred at 25° C. for 12 hours. The solution was diluted slowly with 1 M ethereal HCl (20 ml) and was then stirred for 30 minutes. The solution was filtered and the resulting filtrate was evaporated to dryness to give crude product. Further purification of the material by silica gel chromatography using EtOAc as the eluent provided 3-N-butylsulfonamidoyl)-2,6-dichlorobenzoic acid (Formula 3) (1.43 g, 85%. 1H NMR (DMSO) d 8.11 (t, 1H), 7.98 and 7.71 (doublets, 1H each), 2.75 (m, 2H), 1.55 (m, 2H), 1.32 (m 2H), 0.87 (t, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH2:22][OH:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/CO
Agent: [Mn+4]
Agent: [O-2]
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Yield: 75.2 %

Procedure:
From (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenol (0.301 g) and manganese (IV) oxide (2.101 g) by the process as described for the preparation of Intermediate (9 a) to afford a yellow solid which was purified by FCC eluting with System A (2:3) to afford the title compound (0.225 g) as a white solid, λmax (EtOH) 260.0 (20,050) and 289.2 (inf) nm (ε10,890).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:12]2[O:13][CH2:14][C:15]3[S:19][C:18]([SH:20])=[N:17][C:16]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:20][C:18]2[S:19][C:15]3[CH2:14][O:13][C:12]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=[CH:10][C:11]=4[C:16]=3[N:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1OCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 41 %

Procedure:
Using ethyl[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 41%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: O=C(Nc1cccc2c1C(=O)N(C1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)N(C1CCN(c3ccccn3)CC1)C2=O)c1ccc(Cl)s1

Procedure:
100 mg (0.257 mmol) of 5-chloro-N-[1,3-dioxo-2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-4-yl]-2-thiophenecarboxamide and 0.05 ml (0.513 mmol) of 2-bromopyridine in 0.5 ml of pyridine are stirred at 110° C. for 48 h. The mixture is concentrated and dried under high vacuum. The product is isolated by preparative RP-HPLC.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[N:13]2[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:35])=[C:24]([CH:34]=3)[C:25]([N:27]3[CH2:33][CH2:32][CH2:31][NH2+:30][CH2:29][CH2:28]3)=[O:26])=[CH:15][NH:16][C:17](=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:36].[C:37]([OH:41])(=[O:40])[CH:38]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:37]([CH2:38][NH+:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:25](=[O:26])[C:24]2[CH:34]=[C:20]([CH2:19][C:14]3[N:13]4[C:9]([Cl:8])=[C:10]([Cl:36])[CH:11]=[C:12]4[C:17](=[O:18])[NH:16][CH:15]=3)[CH:21]=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1)([OH:41])=[O:40]
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F)N1CCC[NH2+]CC1
Reactant: O=CC(=O)O
Agent: O=C([O-])C(F)(F)F
Product: O=C(O)C[NH+]1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1

Procedure:
The title compound was prepared as described in Example 2 from Example 8, H3 and glyoxylic acid. 1H NMR (300 MHz, DMSO-d6) δ: 10.96 (1H, d, J=5.6 Hz), 7.37-7.19 (4H, m), 6.64-6.61 (1H, m), 4.42 (2H, s), 4.20 (2H, s), 4.05-3.25 (8H, m), 2.17-1.99 (2H, m). MS (ES) C22H21Cl2FN4O4 required: 494, found: 495 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11](=[O:13])[N:10]=[C:9]2[NH:14][CH3:15])=[CH:4][CH:3]=1.S(OC)(O[CH3:20])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:20])[C:9]2=[N:14][CH3:15])=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: CNC1=NC(=O)CN1c1ccc(Cl)cc1
Product: CN=C1N(C)C(=O)CN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
3 g. of 1-(p-chlorophenyl)-2-methylamino-4-oxo-2-imidazoline and 9 ml. dimethyl sulfate were heated slowly to 120° C. with stirring. The reaction mixture, cooled to room temperature, was filtered. The clear filtrate diluted with 150 ml. H2O was extracted once with 200 ml. ether. The aqueous layer was separated and made basic with 5N NaOH and cooling. The precipitate was filtered and recrystallized once with acetonitrile. Thin-layer chromatography gave a single spot. The yield of product, m.p. 150°-152° C., was 1.6 g. (50%).
Reaction SMILES: [P:1]([NH2:4])([O-:3])[O-:2].[C:5]1([C:16]2[C:25]3[C:20](=CC=CC=3)[CH:19]=[CH:18][CH:17]=2)[C:6]([OH:15])=[CH:7][CH:8]=[C:9]2[C:14]=1C=CC=C2>>[P:1]([NH2:4])([O-:3])[O-:2].[C:25]1([OH:2])[C:16]([C:5]2[C:6]([OH:15])=[CH:7][CH:8]=[CH:9][CH:14]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Agent: NP([O-])[O-]
Product: Oc1ccccc1-c1ccccc1O

Procedure:
As shown in Table 1, the reaction proceeded smoothly at room temperature in the presence of [Ir(cod)Cl]2 (1 mol %) and phosphoramidite ligand 1 above (2 mol %, L/Ir=1) to give after 10 h branched product 3 in 84% isolated yield with excellent regioselectivity (3/4/5=98/1/1) and 95% enantiomeric excess (entry 1). Reaction at 50° C. for 4 h gave 89% of product 3 with 94% ee (entry 2). Reactions catalyzed by complexes of the diastereomeric form of phosphoramidite ligand L1 with opposite relative configuration of the binaphthol and amine unit were slow, even at 50° C., and formed the opposite enantiomer in 66% yield and 75% ee (entry 3). Complexes of binaphthol-derived ligands with achiral and smaller substituents at nitrogen (e.g., phosphoramidite ligand L3) produced lower ee's than did those of phosphoramidite ligand L1 (entry 4). Phosphoramidite ligand L2 with a biphenol unit gave product with a lower, though substantial enantioselectivity of 87% (entry 5).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>CCO>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([C:9](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCN(CC)C(=O)C1CN2CCC1C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)C1CN2CCC1C(=O)C2=Cc1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A mixture of 13 (34.6 g, 154 mmole), benzaldehyde (17.4 g, 164 mmole) and NaOH (6.5 g, 164 mmole) in EtOH (400 ml) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, the resulting yellow crystal was collected by filtration and washed with cold EtOH and dried in vacuo to give 14 (38.4 g, 128 mmole). The filtrate was concentrated under reduced pressure to give a second crop (3.3 g, 11 mmole) (total 41.7 g, 139 mmole, 90%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH2:26])[CH:21]=[CH:22][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClC(Cl)C.CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH:26][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[C:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Reactant: NCCc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cccc(CNCCc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 3-benzoylbenzaldehyde (0.45 g, 2.1 mmol), and (3-chlorophenyl)ethylamine (0.3 ml, 2.1 mmol) and 3 Å molecular sieves (1.0 g) in MeOH (30 ml). Heat to reflux. After 3 hours, cool, filter, and concentrate to give a residue. Dissolve the residue in dichloroethane (20 ml), add acetic acid (0.12 ml, 2.1 mmol) and sodium triacetoxyborohydride (0.6 g, 2.94 mmol) and stir at ambient temperature. After 2 hours, concentrate the reaction mixture and add dichloromethane (90 ml) and extract sequentially with distilled water (50 ml) and then brine (50 ml). Dry the organic layer over Na2SO4 and give a residue. Chromatograph the residue on silica gel eluting with EtOAc to give the title compound as the base.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:31])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([O:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][CH3:28])[CH2:23][CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C.C(OCC)(=O)C>[Cl:2][C:3]1[C:4]([F:31])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([O:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([N:27]([C:45]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:46])[CH3:28])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN[C@H]1CC[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CC[C@H](N(C)C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2600 mg 4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(methylamino)-cyclohexyl-oxy]-7-methoxy-quinazoline-hydrochloride are suspended in 20 ml acetonitrile, then 3.1 ml triethylamine are added and 0.723 ml morpholine-N-carbonyl chloride, dissolved in 5 ml acetonitrile, are added dropwise at <8° C. After stirring overnight at ambient temperature the reaction mixture is diluted with ethyl acetate and the organic phase is extracted with water and saline solution. The organic phase is dried and evaporated down. The residue is stirred out with acetonitrile, the solid is suction filtered and dried.