Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCOC(C)=O.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(Br)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(C#N)ccc1OCc1ccccc1
Temperature: 175 °C

Procedure:
1-Benzyloxy-4-bromo-2-tert-butyl-benzene made in example 47B (319 mg, 1 mmol), zinc cyanide (129 mg, 1.1 mmol) and Pd(PPh3)4 (34.5 mg, 0.03 mmol) were mixed in 4 mL of DMF then the mixture was heated to 175 ° C. in a microwave reactor (Emrys Optimizer by Personal Chemistry) for 5 minutes. The mixture was cooled to room temperature, and then water and EtOAc were added. The EtOAc extracts were dried over Na2SO4, concentrated and the resulting residue was purified by flash chromatography (5–10% EtOAc/Hexanes) to give the desired nitrile (64 mg). MS (DCI) m/z 238 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH2:31])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: Cc1ccc(Sc2ccc(OC(C)C)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(OC(C)C)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (250 mg, 1.56 mmol) was reacted with the product from Example 56a (427 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (185 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.23 (d, J=6.25 Hz, 6H) 2.34 (s, 3H) 2.76 (s, 3H) 4.48-4.58 (m, 1H) 6.27 (d, J=6.99 Hz, 1H) 6.81 (d, J=8.82 Hz, 2H) 7.14 (d, J=8.09 Hz, 1H) 7.22 (d, J=8.82 Hz, 2H) 7.27 (s, 1H) 7.30 (s, 1H) 7.79 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.46 Hz, 1H) 10.99 (s, 1H) 14.36 (s, 1H); MS (ESI+) m/z 416 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, CDCl3) 1.62 (6H, s), 4.50 (1H, s), 7.08 (1H, d, J 7), 7.41 (1H, t, J 9), 7.53-7.64 (4H, m), 7.72 (1H, dd, J 8 and 1), 7.84 (1H, s), 7.86 (1H, s), 8.86 (1H, d, J 7); m/z (ES+) 373 (M++H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([OH:13])=[O:12].[OH-].[Na+]>C(#N)C.CN(C=O)C.[Pd]>[NH:6]1[C:7]2[C:3](=[C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(O)c1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a mixture of 4-bromoindole (11.81 g, 60.26 mmol), and 3-carboxyphenylboronic acid (10.0 g, 60.6 mmol) in acetonitrile (100 mL) and DMF (100 mL) were added Palladium catalyst Pd(PPh3)4 (2.09 g, 1.81 mmol) and the freshly prepared sodium hydroxide solution (9.64 g, 241 mmol in 80 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under argon at 110° C. oil bath for 4 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, filtered through celite, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, dried over MgSO4, and concentrated. The crude product was purified by a silica gel column eluting with DCM: Hexanes: acetic acid (100:1:1) to provide 10.2 g (71%) of 3-(1H-indol-4-yl)-benzoic acid as a gray yellow solid.
Reaction SMILES: [C:1]([C:4](=[CH:10][NH:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[C:5]([O:7]CC)=O)(=[O:3])[CH3:2].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:1]([C:4]1[C:5](=[O:7])[C:13]2[NH:14][N:15]=[CH:16][C:12]=2[NH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1cn[nH]c1)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)c1c[nH]c2cn[nH]c2c1=O
Yield: 74 %

Procedure:
Ethyl 2-acetyl-3-(4-pyrazolylamino)acrylate (D13, 1.0 g, 4.5 mmol) was added to boiling Dowtherm A, and the solution was heated under reflux for 20 min. The mixture was allowed to cool and 60°-80° petroleum ether (100 ml) was added. The solid was filtered off and washed well with petroleum ether to give the title compound (590 mg, 74%), m.p.>320° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[C:20]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:19]=3[CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH:8]=[CH:7][C:6]=1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2].[Br:32]Br>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[C:20]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:19]=3[C:18]([Br:32])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH:8]=[CH:7][C:6]=1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1OC(C)=O
Reactant: BrBr
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1OC(C)=O

Procedure:
Prepared from acetic acid 2-acetoxy-4-(benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (Example 36) according to the procedure of Example 37. White solid: mp 178-179° C.: MS (EI): [M+], 1 bromine isotope pattern, 504, 506; Anal. Calc. for C26H17BrO4S: C, 61.79, H, 3.39, N, 0.00. Found: C, 61.37, H, 3.32, N, 0.11.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:27]=[C:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:27])[CH2:33]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C1CNCCN1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (111 mg, 0.3 mmol) in CH2Cl2 (2 mL) were added 2-oxopiperazine (33 mg, 0.33 mmol), diisopropylethylamine (DIPEA) (80 μL, 0.45 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (130 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 2 h then diluted with CH2Cl2. The organic phase was washed with aqueous water, dried over MgSO4, filtered and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC yielding Compound 69 as a brown solid (69.7 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=O)[C:6]([Cl:8])=[O:7].[N:11]1([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])C=[CH:14][CH:13]=[CH:12]1>ClCCCl>[Cl:8][C:6]([C:5]1[N:11]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of anhydrous aluminium chloride (3.1 g; 4.7×5 mM) in 20 ml of 1,2-dichloroethane was cooled with ice to 0°-5° C., and oxalyl chloride (3 g; 4.7×5 mM) was added dropwise to the suspension. After stirred at 0°-5° C. for 20 minutes, a suspension of N-(1H-pyrrol-1-yl)phthalimide (IX-I; 1.0 g; 4.7 mM) in 1,2-dichloroethane was added thereto. Thereafter, the mixture was stirred for 50 minutes with slowly raising the temperature to room temperature. The reaction mixture was poured into ice water and insoluble materials was removed by filteration. To the filtrate was added ethyl acetate with thoroughly stirring to separate an organic phase. The organic phase was dried with sodium sulfate, and the solvent was then removed by distillation to obtain the compound (IX-61)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=2)=[O:22])[CH:6]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)c1cccc(N)c1
Agent: Cl
Product: COC(=O)c1cccc(NC(=O)CNC(=O)OCc2ccccc2)c1
Yield: 91.1 %

Procedure:
3-Amino-benzoic acid methyl ester hydrochloride (1.88 g, 10.0 mmol) was reacted with N-α-CBZ-glycine (3.14 g, 15.0 mmol) according to the procedure of Example 102, step a to afford the product (3.12 g, 91%). 1H NMR (300MHZ, CDCl3) 10.18 (1H, br s), 8.26 (1H, m), 7.84 (1H, d), 7.65 (1H, d), 7.55 (1H, d), 7.48-7.22 (7H, m), 5.05 (2H, s), 3.85 (3H, s), 3.83 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(O[N:24]1N=N[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:6]
Reactant: COc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 2-chloro-5-methoxy-4-nitro-benzoic acid (200 mg, 0.86 mmol) in acetonitrile (10 mL) was added HBTU (327 mg, 0.86 mmol) followed by aniline (0.08 mL, 0.86 mmol) and diisopropylethylamine (0.56 mL, 3.20 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then heated at 60° C. for 24 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL); the organic layer was separated and washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 75/25) to give 182 mg of 2-chloro-5-methoxy-4-nitro-N-phenyl-benzamide as a light yellow solid.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[N:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:40]C)=[CH:37][CH:38]=3)[CH:33]=[CH:32][C:31]=2[C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH3:51])(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:25][CH:24]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(C)(C)C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[ClH:1].[ClH:1].[CH3:51][S:48]([C:45]1[CH:44]=[CH:43][C:42]([C:31]2[C:30]([O:29][C:26]3[CH:27]=[CH:28][C:23]([NH:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:24][CH:25]=3)=[C:39]3[C:34](=[CH:33][CH:32]=2)[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38]3)=[CH:47][CH:46]=1)(=[O:50])=[O:49]
Reactant: COc1ccc2c(Oc3ccc(N(CCN4CCCCC4)C(=O)OC(C)(C)C)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(NCCN3CCCCC3)cc2)cc1
Yield: 81.8 %

Procedure:
Add 4M HCl/dioxane (3 mL, 12 mmol) to a solution of the compound of Example 57 (10 mg, 0.17 mmol) in dichloromethane (3 mL) and stir the reaction for 40 minutes, then evaporate to dryness under reduced pressure. Dissolve the residue in dichloromethane (4 mL) and add boron tribromide (0.068 mL, 0.72 mmol). Stir the reaction for 3.5 hours, then add aqueous saturated sodium bicarbonate (5 mL) and allow the phases to separate. Dry the organic layer with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/methanol mixtures. Evaporate the fractions containing product to dryness and redissolve in 5% methanol/dichloromethane (3 mL). Add 1M hydrogen chloride in diethyl ether (0.28 mL) then evaporate the solution under reduced pressure to give 82 mg of the title compound (77%). Mass spectrum (ion spray): m/z=517.5 (M+H).
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]>C(OCC)(=O)C.C(O)(=O)CC>[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: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCOC(C)=O
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 92 °C
Yield: 84.4 %

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 8 ml ethyl acetate and 5.0 ml of propionic acid is heated to its boiling point and maintained at this temperature (92° C.) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with ethyl acetate. After drying, 0.92 g of raw deferasirox is obtained, i.e. 84% of the theory, with an HPLC purity of 99.7% and a melting temperature of 258 to 263° C.
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17]#[N:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12>N1C=CC=CC=1.C(N(CC)CC)C>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17](=[S:1])[NH2:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 70 h
Yield: 67 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 5.0 g (0.020 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile in 100 ml of pyridine and 1 ml of triethylamine. The dark brown solution was left to stand for 70 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and extracted. The pale yellow product was chromatographed over silica gel with ethyl acetate as the eluent, stirred vigorously in ether for 16 hrs. and subsequently filtered off under suction. There were obtained 3.8 g (67%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-thiocarboxamide as pale yellow crystals; m.p. 227-230° and [α]D20 =-473.7° (DMF, c=1%).
Reaction SMILES: C([N:4]([C:8]1[C:13](Br)=[CH:12][CH:11]=[CH:10][N:9]=1)C(=O)C)(=O)C.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=O>[Cu]I.O1CCOCC1>[CH3:33][C:31]1[NH:4][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:30]=1[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(=O)N(C(C)=O)c1ncccc1Br
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1[nH]c2ncccc2c1C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 20.2 %

Procedure:
To a 500 mL round-bottom flask that contains N-acetyl-N-(3-bromopyridin-2-yl)acetamide (14.815 g, 57.6 mmol), was added copper(I) iodide (1.098 g, 5.76 mmol), L-proline (1.327 g, 11.53 mmol), cesium carbonate (28.2 g, 86 mmol), then t-butyl acetoacetate (11.47 ml, 69.2 mmol) and dioxane (100 mL). The reaction was vac/purged with N2 3× then fitted with a septum and a N2 inlet and heated overnight at 70° C. The inorganic solids were removed by filtration over celite and the cake was washed with 100 mL EtOAc. This solution was concentrated and the residue was partitioned between 250 mL brine and 250 mL EtOAc. The aq. Layer was further extracted with EtOAc (2×250 mL) and the combined organic layer was dried over Na2SO4, filtered, concentrated and purified by CC using 1:1 EtOAc:Hex as eluent to provide (2.7 g, 20.2%) of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate. LRMS (M+H+) m/z: calc'd 233.28. found 233.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:22]3=[N:21][CH:20]=1)[CH:15]=[CH:14]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].CO>[CH2:28]([C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[CH:20][N:21]=[C:22]2[CH:27]=1)[CH3:29]
Reactant: CCc1ccn2c(-c3ccc4cccc(OCc5ccccc5)c4n3)cnc2c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 8-(benzyloxy)-2-(7-ethylimidazo[1,2-a]pyridin-3-yl)quinoline (3.06 g, 8.06 mmol), Pearlman's catalyst (20% wt Pd, 283 mg) and ammonium formate (5.08 g, 80.6 mmol) in MeOH (50 ml) was degassed under nitrogen and heated at 80° C. for three hours, followed by stirring at ambient temperature overnight. The reaction mixture was poured into excess water and extracted with CH2Cl2 and EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (eluting with MeOH/CH2Cl2) to afford a mixture of starting material and desired product. This mixture was resubmitted to the original reaction conditions and refluxed for four hours. The reaction mixture was poured into excess water and extracted with CH2Cl2 and EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the title compound (768 mg, 33% yield) as a solid. MS APCI (+) m/z 290.3 (M+1) detected.
Reaction SMILES: [H-].[Na+].[CH:3]([NH:5][CH2:6][C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])=[O:4].CI.Cl[CH2:20]Cl>CN(C=O)C>[CH:3]([NH:5][CH:6]([CH3:20])[C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])=[O:4]
Reactant: ClCCl
Reactant: O=CNCC(=O)c1ncn2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(NC=O)C(=O)c1ncn2ccsc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (31 mg) was added to a solution of 0.24 g of 7-formylaminoacetylimidazo[5,1-b]thiazole in 4 ml of DMF. The mixture was stirred at 60° C. for 30 min, and cooled to room temperature. Thereafter, 176 mg of methyl iodide was added thereto. The mixture was stirred for one hr. Dichloromethane was added to the reaction mixture. The mixture was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 0.12 g of 7-(2-formylaminopropionyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.8 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (0.30 g, 1.06 mmol) in anhydrous THF (5 mL) were added dimethyl-piperidin-4-yl-amine (0.27 g, 2.11 mmol), sodium triacetoxyborohydride (0.34 g, 1.60 mmol) and glacial acetic acid (90 μL, 1.59 mmol). The resulting solution was stirred at RT for 17 h, then partitioned between EtOAc and a sat. aqueous solution of NaHCO3. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (0.10 g, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(Br)cc1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
A mixture of 4-bromo-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (710 mg, 1.87 mmol), 1-bromo-2-methyl propane (305 μL, 2.80 mmol) and K2CO3 (412 mg, 2.99 mmol) in DMF (5 mL) was heated at 90° C. for 18 hours. The cooled mixture was diluted with EtOAc, washed with water (3×) and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-15% EtOAc in cyclohexane) and triturating with pentane gave 4-bromo-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (562 mg, 69% yield) as a colourless crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.72-7.55 (m, 2H), 7.57-7.56 (m, 2H), 7.58-7.43 (m, 2H), 7.13-7.09 (m, 1H), 3.53-3.08 (m, 2H), 1.66-1.63 (m, 1H), 0.90 (d, J=6.5 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H), LCMS (m/z, Method A) ES+ 436.0 [M+1]+.