Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:18]([O:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[N+:8]([C:5]1[C:4]([NH2:11])=[CH:3][C:2]([O:32][C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[CH:31][CH:30]=2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Nc1cc(Br)cnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2cnc([N+](=O)[O-])c(N)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
To a solution of 5-bromo-2-nitropyridine-3-ylamine (436 mg, 2.0 mmol) in DMF (10 mL) was added Cs2CO3 (977 mg, 3.0 mmol) followed by 4-(t-butoxycarbonyl)aminophenol (459 mg, 2.2 mmol) in DMF (10 mL) at 0° C. then stirred at room temperature for 3 days. The mixture was extracted with ethyl acetate. The organic layer was washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (624.2 mg, 90%): MS m/e 347 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[S:26][CH:27]=[C:28]([CH2:30][CH3:31])[N:29]=4)=[CH:21][C:20]=3[CH2:32][CH2:33][CH3:34])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O[Li].O>C1COCC1.O>[CH2:30]([C:28]1[N:29]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=[CH:7]4)=[C:20]([CH2:32][CH2:33][CH3:34])[CH:21]=2)[S:26][CH:27]=1)[CH3:31]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To a solution of methyl(5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]propoxy}-1H-indol-1-yl)acetate (Example 53, 89 mg, 0.18 mmol) in 3.0 mL THF, was added LiOH.H2O (30 mg, 0.72 mmol) in water (1.0 mL). The mixture was stirred for 12 h at rt. The solvents were evaporated and the residue was suspended in a small volume of water. The pH of the mixture was adjusted to 3 with 1 N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated to give 65 mg (75%) of the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H), 7.35 (dd, 1H), 7.10-7.05 (m, 2H), 7.08 (d, 1H), 6.90 (dd, 1H), 6.78 (s, 1H), 6.45 (d, 1H), 6.35 (d, 1H), 4.85 (s, 2H), 4.34 (t, 2H), 4.26 (t, 2H), 2.92 (q, 2H), 2.55-2.45 (m, 2H), 2.25-2.15 (m, 2H), 1.62-1.50 (m, 2H), 1.35 (t, 3H), 0.92 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: ClCCN1CCCCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCCC1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=583.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)piperidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:37])[CH:25]=2)=[CH:18][N:17]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:37])[CH:25]=2)=[CH:18][N:17]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: c1ccncc1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccn(Cc3ccccc3)c(=O)c2)c(=O)[nH]1

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamine (1.28 g) and 2-nitroamino-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.47 g) were refluxed in pyridine (12 ml) for 20 hours. The reaction mixture was evaporated under reduced pressure and the glassy residue washed with hot water. The mixture was allowed to cool and the water was decanted to give the title compound as a residue. This residue was taken up in isopropanol, treated with ethanolic HCl, evaporated under reduced pressure and crystallised from ethanol-methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-benzyl-2-oxopyridin 4-ylmethyl)pyrimidin-4-one as a trihydrochloride salt (3.23 g): recrystallisation gave material with m.p. 185.5°-189° C.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[C@@H:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:23]=1[F:30].[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:14][C@H:5]1[CH2:4][C@@H:3]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6]1=[O:13]
Reactant: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)C[C@H](N)C(=O)N1CC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl]carbamate (402 mg, 0.913 mmol) in EtOAc (10 mL) was saturated with HCl (g) and aged for 30 min. The resulting mixture was concentrated in vacuo to give the title compound. MS: m/z=341.0 (M+1); 1H NMR (500 MHz, CD3OD) δ 7.20 (m, 1H), 6.94 (m, 1H), 4.78 (dq, 1H, J=15.4, 9.3 Hz), 4.26 (dd, 1H, J=12.1, 6.7 Hz), 4.08-4.00 (m, 2H), 3.73 (dq, 1H, J=15.4, 8.8 Hz), 2.57 (q, 1H, J=12.5 Hz), 2.36 (ddd, 1H, J=12.5, 6.6, 2.0 Hz), 1.07 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]([F:23])([F:22])[F:21])[C:14]=1[F:24].[CH:27]([Sn](CCCC)(CCCC)CCCC)=[CH2:28].CCOC(C)=O.[Na+].[Cl-]>CN(C=O)C.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>[CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:27]=[CH2:28])=[C:15]([C:20]([F:23])([F:22])[F:21])[C:14]=1[F:24]
Reactant: Cc1ccc(Nc2ccc(Br)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(Nc2ccc(C)cc2CC(=O)N(C)C)c(F)c1C(F)(F)F
Temperature: 120 °C

Procedure:
5-Methyl-2-(2′-fluoro-4′-bromo-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide prepared by method outlined in example 3 (0.8 g, 1.7 mmol), Pd(PPh3)4 (0.1 g, 0.09 mmol), and vinyl tributylstannane (0.6 g, 1.9 mmol) in DMF (5 mL) is heated to 120° C. under nitrogen overnight. After cooling, the reaction is portioned between EtOAc and saturated aqueous solution of NaCl. The separated organic layer is washed twice with fresh saturated aqueous solution of NaCl. The EtOAc layer is dried and concentrated under reduced pressure. The residue is purified by flash chromatography to give 5-Methyl-2-(2′-fluor-4′-vinyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=[O:16].[C:18]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(-c2ccc(Cl)c(C(=O)O)c2)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2cccc(C)c2)ccc1Cl
Yield: 98.4 %

Procedure:
A mixture of 4-chloro-3′-methylbiphenyl-3-carboxylic acid (1.70 g, 6.90 mmol), K2CO3 (7.0 g, 50.6 mmol) and CH3I (3 mL, 48 mmol) in acetone (30 mL) was heated under reflux for 1 h. After filtration and evaporation of excess CH3I, the residue was washed with water and extracted with ethyl acetate, dried over anhydrous Na2SO4, and evaporated solvent in vacuo to provide crude methyl 4-chloro-3′-methylbiphenyl-3-carboxylate (1.77 g, 98%) as a brown oil. 1H NMR (300 MHz, DMSO-d6): δ 8.04 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.52-7.47 (m, 2H), 7.38 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 3.90 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:21]1[C:22](=[O:29])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]1=[O:30])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(Cl)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
To a solution of 64 (13.50 g, 44.28 mmol) and THF (150 mL) cooled to 0° C. was added isoindoline-1,3-dione (7.167 g, 48.71 mmol) and PPh3 (17.42 g, 66.42 mmol) followed by the dropwise addition of a 40% solution DEAD (26.15 mL, 66.42 mmol) in toluene. The reaction was warmed to RT and stirred for 20 h. The reaction was concentrated and dissolved in Et2O (might require sonication). The solids were filtered and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography (Biotage 65) eluting with 10% EtOAc/hexane to afford 14.35 g of (74.67%) (S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)isoindoline-1,3-dione (66).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-])=O)=[C:5]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:6]=[CH:7][N+]([O-])=O>C(O)C.C(O)=O.[OH-].[OH-].[Pd+2]>[CH3:16][O:15][C:12]1[CH:11]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:13]=1[OH:14])[NH:17][CH:7]=[CH:6]2
Reactant: COc1cc(C=C[N+](=O)[O-])c([N+](=O)[O-])c(OC)c1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: COc1cc2cc[nH]c2c(OC)c1O
Yield: 14 %

Procedure:
A mixture of 10 g (0.037 mole) of 3,5-dimethoxy-4-hydroxy-2,β-dinitrostyrene and 10 g of palladium hydroxide on charcoal in 400 cm3 of ethanol and 7 cm3 of formic acid is heated under reflux for 3 hours. After cooling, the reaction mixture is filtered through Celite. The filtrate is evaporated to dryness. The residue is redissolved in dichloromethane and the solution is filtered on silica gel. After distillation of the solvent under reduced pressure and recrystallization from diisopropyl ether, 1 g of the desired product is obtained in the form of a whitish solid (yield=14%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>C(Cl)Cl>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH2:6]1
Reactant: OC1CCNC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
4-hydroxypyrrolidine (12 g, 0.14 mol), DCM (300 ml) and 1N aqueous sodium carbonate solution (200 ml) were charged to a flask and cooled to <10° C. A solution of 4-cyanobenzenesulfonyl chloride (26.8 g, 0.133 mol) in DCM (100 ml) was added dropwise, maintaining the temperature below 10° C. (typically addition takes 40-50 min). Cooling was removed and stirring at room temperature continued for 2 h. The layers were separated, the organic layer was washed with water (2×100 ml) and concentrated in vacuo to approximately 100 ml. Hexane (about 300 ml) was added to initialise crystallisation. The precipitate was aged at 0-5° C. for 10-30 min, filtered and washed with hexane (2×100 ml) to yield 30.3 g (86%) of sulfonamide 4-[(3-hydroxy-1-pyrrolidinyl)sulfonyl]benzonitrile 23a as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.[F:26][C:27]1[CH:32]=[C:31](Br)[CH:30]=[CH:29][N:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([F:26])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Fc1cc(Br)ccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Product: Cc1cc(-c2ccnc(F)c2)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 2-Fluoro-4-bromopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=329.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[C:25]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:23][C:24]1[C:25]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ccc(C(=O)O)c(OCCNC(=O)OC(C)(C)C)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCCNC(=O)OC(C)(C)C)c1
Yield: 79 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(2-tert-butoxycarbonylaminoethoxy)-4-(methylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the desired product as a solid (4.0 g, 79%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9](C(OC(C)(C)C)=O)[CH:8]3[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:7]3[C:6]=2[CH:5]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[C:10]2[NH:9][CH:8]3[CH2:18][CH2:19][NH:20][CH2:21][CH:7]3[C:6]=2[CH:5]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc(Br)c1N2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2cc(Br)c3c(c2)C2CNCCC2N3)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A 100 mL round bottom flask was charged with a solution of di(tert-butyl) 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (0.27 g, 0.45 mmol) in CH2Cl2 (5 mL) and cooled to 0° C. with an ice bath. Trifluoroacetic acid (5 mL) was added via pipette, the ice bath was removed, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction was then concentrated in vacuo, and the residue was partitioned between 5 N NaOH and ethyl acetate (2X). The organics were combined, dried with MgSO4, filtered and concentrated to give 280 mg of a crude yellow oil. The crude was purified on a 40 g silica Biotage column using 5% methanol in CH2Cl2 as the eluent to give 151 mg (85%) of 6-bromo-8-(2,4-dichlorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J=2 Hz, 1 H), 7.26 (m, 3 H), 7.10 (s, 1 H), 4.08 (m, 2 H), 3.28 (m, 1 H), 3.14-2.86 (m, 4 H), 1.93-1.80 (m, 3 H); IR (diffuse reflectance) 2937, 2851, 1615, 1572, 1460, 1359, 1314, 1303, 1237, 1102, 1032, 869, 816, 761, 744 cm−1. OAMS supporting ions at: ESI+398.8; HRMS (FAB) calcd for C17H15BRCL2N2 +H1 396.9874, found 396.9867.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][C:15]1[CH:16]([O:21][CH2:22][CH3:23])[O:17][C:18](=[O:20])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.[H][H].ClCCl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][CH:15]1[CH2:19][C:18](=[O:20])[O:17][CH:16]1[O:21][CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: N#N
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC1OC(=O)CC1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
To a solution of (R )-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (X, R1=Et) (0.09 g, 0.27 mmol) in toluene previously degassed with N2 (20 mL) in a high pressure reactor in a nitrogen filled glove bag, was added (−)-1,2-bis((2R,5R)-2,5-diethyl-phospholano)benzene-(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (5-15 mg). The reactor was sealed and pressurized with hydrogen (950 psi, 65 atm) and was let stand at room temperature for 2 d. Solvent was evaporated and the residue was purified by flash chromatography (SiO2) eluted with 1.5:98.5 methanol:dichloromethane to provide (R)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.092 g, quant yield) as a colorless oil. Chiral HPLC (chiralpak-AD column, eluted with 1:9 ethanol:hexanes): isomer Ib-35.4%, isomer Id-56.4%, (mixture of isomers Ia and Ic)-8.2%. 1H-NMR (500 MHz, CDCl3) δ 7.60 (br s, 0.25H), 7.40 (br s, 0.25H), 6.5 (br m, 0.25H), 5.38 (d, J=5 Hz, 0.5H), 5.27 (s, 0.5H), 4.65 (br, 0.5H), 4.20 (br m, 1.5H), 3.85 (m, 0.5H), 3.77 (m, 0.5H), 3.57 (m, 1H), 3.30 (m, 2H), 2.95 (m, 0.5H), 2.80 (br m, 0,5H), 2.30 (br m, 2H), 1.85 (br s, 3H), 1.37 (s, 9H), 1.20 (t, J=7 Hz, 1.5H), 1.15 (t, J=7 Hz, 1.5H) ppm.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CN(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCCN(C)C)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (100 mg, 0.234 mmol) in DMF (5 mL) were added 3-(dimethylamino)-1-propanol (121 mg, 1.170 mmol), EDC (90 mg, 0.468 mmol) and DMAP (2.86 mg, 0.023 mmol). The resulting mixture was stirred at room temperature overnight, the reaction mixture was concentrated in vacuo, dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (HpH). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(dimethylamino)propyl 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (23 mg, 19%) as a colourless oil. LCMS (Formate, 2 min), Rt=0.70 min, MH+=513.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][CH2:10][Br:9]
Reactant: BrCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: BrCCOc1ccccc1Br
Temperature: 80 °C

Procedure:
A suspension of 2-bromophenol (3.50 g, 20.23 mmol), 1,2-dibromoethane (19.00 g, 101 mmol), and potassium carbonate (7.06 g, 2.92 mmol) in acetonitrile (50 mL) was heated to 80° C. After heating overnight, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a clear oil. Yield: 6.36 g, 100%. 1H NMR (400 MHz, CDCl3) δ 3.69 (dd, J=6.6, 6.4 Hz, 2H), 4.35 (dd, J=6.7, 6.4 Hz, 2H), 6.87-6.94 (m, 2H), 7.25-7.30 (m, 1H), 7.56 (dd, J=7.9, 1.6 Hz, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=3[CH:12]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (134.8 g) in N,N-dimethylformamide (850 m) was cooled in an ice bath under a nitrogen atmosphere. Potassium tert butoxide (75.2 g) was added in portions such that the temperature did not exceed 22° C. and the resulting mixture was maintained at 0° C. for a further 1.5 hours when 4-fluorobenzotrifluoride (100 g) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water (200 ml) was added and the mixture was extracted with tert butyl methyl ether (1×400 ml, 1×300 ml, 1×200 ml). The combined organic extracts were washed with water (2×400 ml), brine (200 ml) and then dried over magnesium sulphate and evaporated in vacuo to leave the title compound as an off-white/pale yellow solid (206.4 g)