Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[SH:40]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]([F:31])([F:42])[F:41])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:26][CH2:27]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: FC(F)(F)Oc1ccccc1S
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccccc2OC(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2-trifluoromethoxy-benzenethiol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2-trifluoromethoxy-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless foam. MS: 470.3 [M−H]−.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]>C(O)(=O)C.ClCCl>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(O)c(OC)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cc(OC)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of fuming nitric acid (12.1 ml; s.g. 1.5) in glacial acetic acid (120 ml) was added in one portion to a stirred solution of 4-ethyl-2-methoxyphenol (41.7 g) in dry dichloromethane (800 ml). After 1 minute the solution was washed with water (3×300 ml), and the organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give an orange crystalline residue. This was recrystallised from a mixture of methanol and water to give 4-ethyl-2-methoxy-6-nitrophenol (31.3 g), m.p. 59°-61° C.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH3:11])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: C[C@H](CC(F)(F)F)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
To (2S, 3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol (1.07 g, 6.25 mmol) and triethylamine (0.87 mL, 6.2 mmol) in CH2Cl2 (15 mL) at 0° C. was added dropwise a solution of 5-chlorothiophene-2-sulfonylchloride (1.34 g, 6.25 mmol) in CH2Cl2 (15 mL). The reaction mixture was warmed to 25° C. and stirred for 24 h. It was then diluted with EtOAc (100 mL) and washed with aqueous 0.1 N HCl (50 mL) and brine (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried using Na2SO4 and concentrated. Flash chromatography (eluent: 3:7 EtOAc-hexane) provided 5-chloro-N-[(1S, 2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (1.66 g, 75%) as a white solid. Recrystallization (EtOAc-heptane, 1:4) provided white needles (1.39 g, 84% recovery), mp 136–137° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34](=[O:35])[CH2:33][C:27]5([OH:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CC1(O)CCCCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1(O)CCCCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (21.3 mg, 64.7%), MS (ISP) m/z=471.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-(1-hydroxycyclohexyl)acetic acid
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:5]([NH:7][N:8]=[C:9]([CH3:11])[CH3:10])=[O:6].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:9]([CH3:11])([CH3:10])[N:8]([C:16](=[O:18])[CH3:17])[N:7]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=NNC(=O)c1ccc(C)c(Br)c1
Product: CC(=O)N1N=C(c2ccc(C)c(Br)c2)OC1(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-4-methyl-N′-(propan-2-ylidene)benzohydrazide (2.0 g, 7.46 mmol), as obtained hereinbefore, and acetic anhydride (30 mL) was refluxed for one hour. The excess of acetic anhydride was removed under vacuum after cooling the reaction mixture to room temperature and the crude residue obtained was triturated with hexane to remove traces of acetic anhydride present in the reaction mixture. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, 13% ethyl acetate in hexane) to afford 800 mg of the desired product as an oil. 1HNMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 2.44 (s, 3H), 2.29 (s, 3H), 1.85 (s, 6H); ESI-MS (m/z) 311, 313 [(MH)+, Br79,81].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]1[C:68]([CH3:69])=[CH:67][C:66]([C:70](Cl)=[O:71])=[N:65]1>ClCCl>[CH3:63][N:64]1[C:68]([CH3:69])=[CH:67][C:66]([C:70]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:71])=[N:65]1
Reactant: Cc1cc(C(=O)Cl)nn1C
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 63 mg, 0.13 mmol), TSTU (O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 78 mg, 0.26 mmol), and diisopropylethylamine (0.14 mL, 0.8 mmol) in dichloromethane (4 mL) was shaken at room temperature for 3 h. 1,5-Dimethyl-1H-pyrazole-3-carbonyl chloride (available from Maybridge, Tintagel, Cornwall, UK; 23 mg, 0.16 mmol) was added and the mixture was shaken at room temperature overnight. The solution was diluted with dichloromethane (˜6 mL) and washed with water (2×5 mL), 1 M aqueous hydrochloric acid (5 mL), water (5 mL), saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was evaporated and the crude product was purified by HPLC to give (1,5-dimethyl-1H-pyrazol-3-yl)-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone (28 mg, 43%) as a white solid. Mass spectrum (ES) MH+=496.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C.ClCCl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)cc1)NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To a mixture of 0.35 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.17 g of 4-chlorophenylacetic acid, 0.18 ml of triethylamine and 10 ml of dichloromethane was added 0.23 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-chlorophenylacetamido)propyloxy)benzene (70% yield), m.p., 108.4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:5].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1.Cl>C(#N)C>[Cl:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:5][C:4]3[CH:6]=[C:7]([CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[C:8]([N:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:24][CH:25]=[N:26]2)=[CH:31][CH:30]=1
Reactant: Cc1cc(N)cc(CN2CCCC2)c1N1CCN(C)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(Nc2ccnc3cc(Cl)ccc23)cc(CN2CCCC2)c1N1CCN(C)CC1
Yield: 85.2 %

Procedure:
3-Methyl-4-(4-methylpiperazin-1-yl)-5-(pyrrolidin-1-ylmethyl)aniline (70 mg, 0.24 mmol) and 4,7-dichloroquinoline (50 mg, 1 eq) were refluxed overnight in 5 mL of acetonitrile with 1.25 mL of HCl 1M. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a white solid (92 mg, 84% yield). m/z (ESI) 450.1 [M+H]+;
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.P(=O)(O)(O)O.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][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: Br
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Br)sc2c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Into a 150 mL beaker, 2-amino-6-nitrobenzothiazole (5.1089 g, 25.39 mmol, 1 eq) was mixed vigorously with phosphoric acid, 85 wt. % (22.6 mL, 13 eq) at 50° C. The solution was then cooled to −20° C., using an acetone/dry ice bath. To this, a solution of NaNO2 (1.943 g, 28.16 mmol, 1.1 eq) in water (5.0 mL), also cooled to −20° C., was added slowly over the course of 15 min. After 1 h, the resulting suspension was poured over a solution of CuBr (4.593 g, 32.02 mmol, 1.3 eq) in 48% HBr (25.3 mL) at rt and was stirred. Additional HBr (≈35 mL) aided in transfer. After 1 h, the mixture was heated at 40° C. for 2 h. After 2 h, the heat was turned off and the reaction continued to stir at rt for 16 h. The crude mixture was diluted with water to a final volume of 200 mL and was extracted with DCM (3×). The organics were dried over anhydrousmg2SO4, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with DCM/Hex 1:1→2:1→neat DCM]. Fractions containing product were combined, concentrated in vacuo, and re-chromatographed to give the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ=8.11 (d, J=9.2 Hz, 1H), 8.38 (dd, J=9.2, 2.4 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). MS (ES+): m/z 258.95/260.96 (100/96) [MH+]. HPLC: tR=3.43 min (ZQ2000, polar—5 min).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-trifluoromethylphenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. After drying under vacuum, the hydrochloride salt of the title compound was obtained as a colourless solid; MS (ES+) 365 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](O)=[O:23]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[O:23])[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccs1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccs2)ncn1Cc1ccccc1
Yield: 60 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.14 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and 2-thiophenecarboxylic acid instead of 3-pyridylacetic acid hydrochloride to obtain 1.97 g of 1-benzyl-4-(2-thienylcarbonylamino)-5-imidazolecarboxamide (yield 60%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([S:34][CH3:35])=[C:17]([S:19]([C:22]2[CH:27]=[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)(=[O:21])=[O:20])[CH:18]=1)=[O:13].[C:36]([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CCOC(C)=O.C(O)C>[CH2:10]([O:11][C:12]([C:14]1[S:15][C:16]([S:34][CH3:35])=[C:17]([S:19]([C:22]2[CH:23]=[C:24]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:25]=[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:27]=2)(=[O:21])=[O:20])[CH:18]=1)=[O:13])[CH3:36]
Reactant: OB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)cc(OC(C)(C)C)c2)c(SC)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(S(=O)(=O)c2cc(OC(C)(C)C)cc(-c3ccccc3)c2)c(SC)s1
Yield: 65.9 %

Procedure:
The procedure used in Example 1: step d was followed using benzeneboronic acid (42 mg, 0.35 mmol), 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step c) (83 mg, 0.17 mmol)), Na2CO3 (2M, 1.4 mL, 2.8 mmol), Pd(PPh3)4 (48 mg, 0.04 mmol), toluene (5.6 mL), and ethanol (2.8 mL). Analogous aqueous workup and SiO2 flash chromatography (20% EtOAc in hexanes) yielded the title compound (55 mg, 65%). 1H-NMR (CDCl3): δ 8.03 (s, 1H), 7.91 (t, 1H, J=1.6 Hz), 7.63 (t, 1H, J=2.0 Hz), 7.57 (m, 2H), 7.47 (m, 2H), 7.41 (m, 2H), 4.33 (q, 2H, J=7.2 Hz), 2.60 (s, 3H), 1.42 (s, 9H), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[N:23]=3)[N:18]=[CH:17][C:16]=2[C:26]([O:28]CC)=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-].Cl>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[N:23]=3)[N:18]=[CH:17][C:16]=2[C:26]([OH:28])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(C(=O)O)cnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Crude ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-6-chloro-1,5-naphthyridine-3-carboxylate (54) (240.8 g, 554 mmol) was suspended in a 1:1:1 mixture of MeOH:THF:H2O (500 mL each) and LiOH (39.8 g, 1.66 mol, 3 eq) was added. The mixture was maintained at rt and monitored by LCMS. After consumption of starting material, the volatiles were removed under vacuum and the resultant solution was neutralized by the addition of 6N HCl (˜3 eq). The mixture was then carefully acidified to pH 3-5 with 5N HCl (aq). The resultant slurry was then filtered and the precipitate was rinsed with water and then methanol. The resultant precipitate was dried in a vac-oven overnight, to give 203.6 g (83%, over two steps) of 4-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-6-chloro-1,5-naphthyridine-3-carboxylic acid (55).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[Si:29]([O:36][C:37]1[CH:38]=[C:39]([CH:68]=[CH:69][CH:70]=1)[C:40]([NH:42][NH:43][C:44](=[O:67])[C@H:45]([NH:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]#[N:64])=[C:59](Cl)[C:58]=1C)[C@@H:46]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH3:47])=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[CH2:71]([Cl:73])Cl>>[Si:49]([O:48][C@@H:46]([CH3:47])[C@@H:45]([NH:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]#[N:64])=[C:71]([Cl:73])[C:62]=1[CH3:61])[C:44]1[O:67][C:40]([C:39]2[CH:68]=[CH:69][CH:70]=[C:37]([O:36][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[CH:38]=2)=[N:42][N:43]=1)([C:52]([CH3:55])([CH3:53])[CH3:54])([CH3:50])[CH3:51]
Reactant: ClCCl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (polymer bound, 3.0 mmol/g loading) (100 mg, 0.3 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (3 Followed by addition of solid iodine (76 mg, 0.30 mmol). This was allowed to stir at room temperature for a period of 10 min followed by slow addition of triethylamine (0.17 mL, 1.2 mmol). This mixture was allowed to stir at room temperature for an additional ten min. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (95 mg, 0.15 mmol) was taken up in methylene chloride (5 and slowly added to the heavily stirred reaction mixture. After a period of 20 min, the solid polymer was filtered out and washed with additional methylene chloride (20 mL). The organic filtrate was then washed with 10% sodium thiosulfate/water (2×10 mL), brine (1×20 mL) and dried (Na2SO4). The solution was then filtered and concentrated under reduced to reveal a brown oil/solid, which was purified via silica gel chromatography eluted with 20% EtOAc/hexanes to provide the title compound as a white solid (63 mg, 68%): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.52 (m, 1H), 7.38 (m, 1H), 7.33 (m, 2H), 6.99 (m, 1H), 6.46 (d, J=8.6 Hz, 1H), 5.37 (d, J=8.8 Hz, 1H), 4.80 (dd, J=1.8, 8.8 Hz, 1H), 4.54 (m, 1H), 2.37 (s, 3H), 1.42 (d, J=6.2 Hz, 3H), 0.98 (s, 9H), 0.86 (s, 9H), 0.19 (s, 6H), 0.06 (s, 3H), −0.20 (s, 3H).
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]>CN(C)C=O.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: CN(C)C=O
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 80.7 %

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 ml of N,N-dimethylformamide and 5 ml of propionic acid is heated up to 150° C. The mixture is maintained at this temperature and stirred for 1.5 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.88 g of raw deferasirox is obtained, i.e. 81% of the theory, with an HPLC purity of 93% and a melting temperature of 255 to 262° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:19][C:14]4[CH:15]=[N:16][N:17]=[CH:18][C:13]=4[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C(Cl)Cl.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.O>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])[CH:10]=2)[CH2:6][C:7]21[CH2:19][C:14]1[CH:15]=[N:16][N:17]=[CH:18][C:13]=1[CH2:12]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12Cc1cnncc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4cnncc4C2)C3)c1
Temperature: 110 °C
Reaction time: 0.03 h
Yield: 60.2 %

Procedure:
A 10 mL microwave tube was charged with 6′-bromo-5,7-dihydrospiro[cyclopenta[d]pyridazine-6,2′-inden]-1′(3′H)-one (0.0600 g, 0.19 mmol), 3-cyanophenylboronic acid (0.1221 g, 0.83 mmol), Cs2CO3 (0.2822 g, 0.87 mmol), 1,4-dioxane (4 mL), water (1 mL), and PdCl2(PPh3)2 (0.0360 g, 0.05 mmol). The tube was heated in a CEM microwave reactor at 110° C. for 30 min. The reaction mixture was diluted with CH2Cl2 and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ μm 19×50 mm column, 10%→90% MeOH/H2O, 0.1% CF3COOH over 8 min and then 90% MeOH/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0386 g (60%) of 3-(1′-oxo-1′,3′,5,7-tetrahydrospiro[cyclopenta[d]pyridazine-6,2′-inden]-6′-yl)benzonitrile. LC-MS tR=1.43 min in 3 min chromatography, m/z 338 (MH+).
Reaction SMILES: Cl(=O)=O.[S:4](=[O:8])(=[O:7])([OH:6])[OH:5].[Cl:9]([O-:12])(=[O:11])=[O:10].[Na+:13]>>[Cl:9]([OH:12])(=[O:11])=[O:10].[S:4]([O-:8])([O-:7])(=[O:6])=[O:5].[Na+:13].[Na+:13]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=S(=O)([O-])[O-]
Product: [O-][Cl+2]([O-])O

Procedure:
The production of chlorine dioxide at pulp mills involves two main steps. In a first step, sulfuric acid reacts with sodium chlorate to produce chloric acid and sodium sulfate by-product (Reaction 1). In a second step, the chloric acid is reduced to chlorine dioxide by reacting with a reducing agent such as methanol, sulphur dioxide, chloride or hydrogen peroxide (Reaction 2).