Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7](=[CH:12][C:13]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7](=[CH:12][C:13]=1[C:14]([CH3:17])([CH3:15])[CH3:16])[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(C)(C)C)cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(C(C)(C)C)cc1C(=O)OC
Reaction time: 16 h

Procedure:
Dimethyl 4-nitro-5-t-butylphthalate (42 g.) was mixed with 0.2 g. of 5% Pd/C and, while kept under argon, 200 ml. of methanol was added. Rapid stirring under 30 psi of hydrogen gave complete reduction after 20 hours at 35° C. The mixture was filtered through Celite, and the methanol removed under reduced pressure. The residue was dissolved in 250 ml. of hot benzene, filtered, and mixed with 500 ml. of hexane. After standing 3 hours at room temperature and 16 hours at -10° C., the crystalline product was filtered off. After drying, 35.8 g. (95%) of solid dimethyl 4-amino-5-t-butylphthalate remained, m.p. 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:16][CH2:15]2)[C:10]1=[O:31].O.C(O)(C(F)(F)F)=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(F)(F)F)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)CCN1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a mixture of (R)-3-(3,5-Dichloro-4′-trifluoromethyl-biphenyl-4-ylmethyl)-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one (0.12 g) in THF (6 mL), add water (6 mL) and TFA (2 mL). Stir the mixture at room temperature for 12 hours. Dilute the reaction mixture with ethyl acetate and wash with sodium bicarbonate (Sat.) and water. Separate the organic and dry over sodium sulfate, filter and concentrate. Purify the crude mixture on silica gel column with 50% ethyl acetate in hexane to 100% ethyl acetate to afford 0.088 g of the titled product. MS (m/z): 487 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccc(F)cc1F
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(2-Bromo-1-methyl-vinyl)-2,4-difluoro-benzene (279 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-2% MeOH-DCM. The product was further purified by HPLC. Yield: 12 mg. 1H NMR (CD3OD, freebase) δ (ppm): 7.58 (m, 2H), 7.40 (s, 1H), 7.14 (s, 1H), 7.12 (d, 1H), 7.05 (m, 2H), 3.70 (s, 2H), 2.95 (m, 2H), 2.85 (m, 2H), 2.40 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([S:39]([N:42]2[CH2:45][CH2:44][CH2:43]2)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1F.[H-].[Na+].[Cl-].[NH4+]>CN1CCCC1=O>[N:42]1([S:39]([C:34]2[CH:35]=[CH:36][C:37]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[C:32]([F:31])[CH:33]=2)(=[O:41])=[O:40])[CH2:45][CH2:44][CH2:43]1
Reactant: O=S(=O)(c1ccc(F)c(F)c1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (65.0 mg, 0.151 mmol) synthesized in Example (38d) and 1-[(3,4-difluorophenyl)sulfonyl]azetidine (42.3 mg, 0.181 mmol) synthesized in Example (56a) were dissolved in N-methylpyrrolidone (5.0 mL), and sodium hydride (55%, 20 mg, 0.45 mmol) was added, followed by stirring at 100° C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified twice using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-35%) to afford the desired compound (35.6 mg, yield 43%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[C:3]=1[F:14].Cl.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[CH:18]([CH2:24][C:25](O)=[O:26])[CH2:17]2.C(N=C=NC(C)C)(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23]1)[CH:18]([CH2:24][C:25]([O:1][C:2]1[C:3]([F:14])=[C:4]([F:13])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([F:12])[C:10]=1[F:11])=[O:26])[CH2:17]2
Reactant: O=C(O)c1c(F)c(F)c(O)c(F)c1F
Reactant: O=C(O)CC1CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(C(=O)O)c(F)c1F
Reaction time: 8 h
Yield: 235.9 %

Procedure:
2 g of the polymeric support resin from Example 8A (loading about 1.36 mmol/g, 2.72 mmol) are suspended in 20 ml of DMF and shaken with 1.23 g (5.98 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acid hydrochloride and 130 mg (1.09 mmol) of DMAP for 10 min. Then 1.06 ml (6.80 mmol) of N,N′-diisopropylcarbodiimide are added, and the mixture is shaken overnight. The resin is filtered off with suction, washed twice each with 20 ml each of DMF, THF and DCM and dried under high vacuum. 2.318 g of the polymer-bound title compound are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=O)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:19].N1CCCCC1>CO>[C:18](/[C:20](=[CH:9]\[C:8]1[CH:11]=[C:12]([O:13][CH3:14])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])/[C:21]([O:23][CH3:24])=[O:22])#[N:19]
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCl
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Yield: 27.1 %

Procedure:
To a mixture of 3.00 g (11.58 mmol) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde and 1.5 mL (16.95 mmol) of methyl cyanoacetate in 30 mL of methanol is added 0.3 mL of piperidine. The mixture is heated at reflux for 5 minutes then cooled slightly and the thick suspension is collected by filtration washing with ethyl acetate followed by diethyl ether to give 1.07 g (27%) of methyl (2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate as a yellow solid, mp softens at 121° C., melts at 157–160° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:12]2[N:13]=[C:14]([NH2:16])[S:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)(=O)=O.[N-:17]=[N+]=[N-].[Na+].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.O>[NH2:17][CH2:6][CH:7]1[C:12]2[N:13]=[C:14]([NH2:16])[S:15][C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCCc2sc(N)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: NCC1CCCc2sc(N)nc21
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methyl methanesulfonate (3.3 mmol) in DMF (10 mL) was added NaN3 (0.21 g, 3.3 mmol). The resulting mixture was stirred at 85° C. for 30 minutes. The mixture was poured into water (100 mL) and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was dissolved in THF (20 mL) and H2O (10 mL), Na2CO3 (0.35 g, 3.3 mmol) and PPh3 (0.8 g, 3 mmol) was added. After stirring overnight, the reaction mixture was diluted with water (100 mL) and then filtered. The filtrate was extracted with EtOAc, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained and used directly in the next step without further purification.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].FC(F)(F)C(O)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](C=C)[CH:27]=1.O>ClCCl>[Br:25][C:26]1[CH:27]=[C:28]([CH2:2][CH:1]=[O:4])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)[O-]
Reactant: C=Cc1cccc(Br)c1
Agent: [Pb+4]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of lead tetraacetate (3.6 g, 8.2 mmol) and trifluoroacetic acid (8.25 mL) at 0° C. is treated dropwise with a solution of 1-bromo-3-vinylbenzene (1.5 g, 8.2 ml) in dichloromethane, allowed to warm to room temperature, stirred for 2 h at room temperature, diluted with dichloromethane, poured into water, stirred vigorously and filtered through a pad of celite. The filtrate is separated. The filtercake is rinsed with additional portions of dichloromethane. The combined organic phases are washed sequentially with water, NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to afford (3-bromophenyl)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]([Cl:20])=[CH:3][CH2:4][O:5][C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14]O)=[C:8]([Cl:19])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41]>C(Cl)Cl>[Cl:1][C:2]([Cl:20])=[CH:3][CH2:4][O:5][C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:41])=[C:8]([Cl:19])[CH:7]=1
Reactant: OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Yield: 144.2 %

Procedure:
A stirred solution of 7.3 grams (0.020 mole) of 4-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]butan-1-ol in 400 mL of methylene chloride was cooled in an ice bath and, in turn, 5.5 grams (0.021 mole) of triphenylphosphine and 6.9 grams (0.021 mole) of carbon tetrabromide were added. Upon completion of addition the reaction mixture was stirred with continued cooling for one hour, then it was allowed to warm to ambient temperature where it stirred during an 18-hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using hexane and a mixture of 1:1 methylene chloride and heptane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 12.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)(=[O:40])=[O:39]
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.063 g) in CH2Cl2 (6 mL) was added DIEA (0.05 mL) and methanesulfonyl chloride (0.015 mL). After 1 hour, the mixture was concentrated and purified by chromatography (Silica gel: 4% MeOH/CH2Cl2, Chromatotron) afforded the titled compound. (0.069 g). MS (m/z) 546 (MH+). mp 229 CC.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7](Cl)[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].ClC1C=C(C=C(Cl)C=1)N>>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: Nc1cc(Cl)cc(Cl)c1
Product: Nc1cc(Cl)cc(Cl)c1Cl
Yield: 37.5 %

Procedure:
Under these conditions, it is observed that the degree of conversion (DC) of the 2,3,4,5-tetrachloroaniline is 99.5% and the actual yield of 3,5-dichloroaniline is 61.1%; 37.5% of 2,3,5-trichloroaniline, formed as an intermediate, remains.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[K+]>C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[O:19]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:16][CH2:21][C:22]([OH:24])=[O:23])=[C:10]([Cl:17])[C:9]=2[Cl:18])[CH2:14][CH2:15][CH:6]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CCC1C1CCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Reaction time: 3 h

Procedure:
2-Cyclopentyl-6-hydroxy-7,8-dichloro-1-tetralone (9.45 g., 0.03 mole) is heated in a mixture of potassium carbonate (5.52 g.) and ethyl bromoacetate (6.68 g., 0.04 mole) in DMF 70 ml.) at 55°-60° C. for three hours. Potassium hydroxide (2.24 g., 0.04 mole) is added. This solution is added to the reaction mixture and the whole is refluxed for 1 hour. Most of the methanol is evaporated and the residue is added to water (ca. 200 ml.). The solid that separates upon acidification is collected, washed with water and crystallized from ethanol to obtain (1-oxo-2-cyclopentyl-7,8-dichloro-1,2,3,4-tetrahydro-6-naphthyloxy)acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH:18]([OH:19])[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCc1ccc(Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)[C@H](CCc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cooled solution of [(5)-3-(4-bromo-phenyl)-1-formyl-propyl]-carbamic acid tert-butyl ester (7.3 g) in THF (40 ml) and Et2O (30 ml) at 0° C. was added dropwise over 30 min a solution of methylmagnesium bromide (20.0 ml, 3 M solution in Et2O). The reaction mixture was then stirred at room temperature for 4 hours before being quenched by dropwise addition of water (gas formation!). The reaction mixture was then poured into EtOAc, the layers were separated and the organic layer was washed sequentially with diluted aq. HCl (pH 5) and saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 80% EtOAc in hexane) to afford {(1S,2RS)-1-[2-(4-bromo-phenyl)-ethyl]-2-hydroxy-propyl}-carbamic acid tert-butyl ester as a colourless amorphous solid comprising a mixture of epimers (5.1 g, 66%). MS (EI): 303 ([{81Br}M−C4H8]+), 301 ([{79Br}M−C4H8]+), 258 ([{81Br}M−C4H8—CO2H]+), 256 ([{79Br}M−C4H8—CO2H]+), 214, 212, 171, 169, 57 ([C4H9]+).
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[CH:30]([O:33][C:34]1[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)[N:35]=1)([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:41][CH2:40][C:38]1[CH:37]=[C:36]([C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:47]=2)[N:35]=[C:34]([O:33][CH:30]([CH3:32])[CH3:31])[CH:39]=1)=[O:7])[CH3:2]
Reactant: CC(C)Oc1cc(CN)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(OC(C)C)nc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 16.2 %

Procedure:
A solution of acid 4B (300 g, 1.09 mmol) in THF (15 mL) was added with DEPC (0.21 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27M (370 mg, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (3/7 EtOAc/Petroleum ether) to afford a white solid (100 mg) after crystallization from ethyl ether. Yield=18%. 1HNMR (DMSO, 400 MHz) δ 1.08 (t, 3H, J=7.4), 1.26 (d, 6H, J=6.2), 3.39 (q, 2H), 4.40 (d, 2H, J=7.9), 5.13 (s, 1H), 5.39 (m, 1H), 6.12 (s, 1H), 6.65 (s, 1H), 7.42 (t, 3H, J=4), 7.56 (s, 1H), 7.86 (m, 4H), 8.23 (d, 2H, J=8), 8.79 (t, 1H). [M+1] 565.02 (C27H27F4N3O4S requires 565.58).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1B(O)O.[C:13]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[CH:26]=[C:25]3[O:30][CH2:31][O:32][C:24]3=[CH:23][C:22]=2[CH:21]1[CH2:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[CH:26]=[C:25]3[O:30][CH2:31][O:32][C:24]3=[CH:23][C:22]=2[CH:21]1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])=[CH:38][CH:39]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2C1Cc1ccc(Br)cc1)OCO3
Reactant: COc1ccncc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: COc1ccncc1-c1ccc(CC2c3cc4c(cc3CCN2C(=O)OC(C)(C)C)OCO4)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 4-methoxy pyridine-3-boronic acid hydrate 19 (0.716 g, 4.684 mmol), 5-(4-bromobenzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinoline-6-carboxylic acid tert-butyl ester 38 (1.043 g, 2.342 mmol), Palladium(II) acetate (0.021 g, 0.094 mmol), triphenylphosphine (0.049 g, 0.187 mmol) and Na2CO3 (0.993 g, 9.368 mmol) in anhydrous 2-propanol (20 mL) was refluxed for 16 h. The reaction mixture was cooled to room temperature, filtered through silica, washed with ethyl acetate. The solvents were concentrated under reduced pressure. The crude residue was purified by flash column chromatography using Acetone-Hexanes (20:80 to 50:60 v/v) to yield 43 (0.389 g, 35%). MS (ES+) m/z 497 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:3]([F:27])=[C:4]2[O:9][CH2:8][C:7]3([CH2:12][CH2:11][CH2:10]3)[N:6]3[CH:13]=[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:15](=[O:21])[C:16]([C:17]=1[N+:18]([O-])=O)=[C:5]23.[H][H]>CN(C=O)C.[Pd]>[NH2:18][C:17]1[C:16]2[C:15](=[O:21])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][N:6]3[C:7]4([CH2:12][CH2:11][CH2:10]4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([F:27])[C:2]=1[F:1]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CCC1
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of ethyl 9′,10′-difluoro-8′-nitro-7′-oxospiro[cyclobutane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (580 mg, 1.53 mmol) in DMF (30 mL) was treated with hydrogen under atmospheric pressure over 10% Pd/C (60 mg) at 50° C. for 3 hours. The catalyst was removed by filtration with Celite and the filtrate was poured into ice-water. The resulting precipitate was stirred for 1 hour and collected by filtration, washed with water and dried to yield the title compound (468 mg, 88%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (3H, t, J=7.3 Hz), 1.92-2.02 (2H, m), 2.10-2.19 (2H, m), 2.61-2.69 (2H, m), 4.23 (2H, q, J=7.3 Hz), 4.39 (2H, s), 7.38 (2H, brs), 8.65 (1H, brs). ESIMS (+): 351 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])=S)[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.C1(S(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]2[N:28]=[C:29]([NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(I)cnc1NCc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a stirred solution of ethyl N-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate (2.30 g, 3.69 mmol) and triethylamine (1.30 g, 1.8 mL, 12.85 mmol) in tetrahydrofuran (20 mL) was added benzenesulfonyl chloride (0.93 g, 5.27 mmol). The resulting mixture was allowed to stir at room temperature. After 12 h, a precipitate had formed. The mixture was filtered, and the filtercake was washed with water (2×10 mL) and methanol (10 mL). The solids were dried to provide 1.50 g (69%) of ethyl (6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[CH3:32]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([CH3:32])[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(C)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-chloro-3-methylphenylboronic acid (145 mg, 0.85 mmol) the subtitle compound was obtained (85 mg, 25%). MS 395 m/z (M+H)+.