Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC([Si](C)(C)[O:29][C@H:30]1[CH2:34][NH:33][C:32](=[O:35])[CH2:31]1)(C)C>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:33]5[CH2:34][C@H:30]([OH:29])[CH2:31][C:32]5=[O:35])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: O=C1C[C@@H](O)CN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 252 (E252) was prepared from 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and (4R)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-pyrrolidinone (Tetrahedron, 2000, 56(39), 7705-7713) using the method described in E251; MS (ES+) m/e 394 [M+H]+.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:15]=[O:16])[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.[BH4-].[Na+].O>C(O)C>[I:1][C:2]1[N:3]=[C:4]([CH2:15][OH:16])[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(I)nc1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.2 %

Procedure:
4-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (4.6 g, 13.1 mmol) was dissolved in ethanol (50 ml) under argon. Sodium borohydride (0.514 g, 13.1 mmol) was added and the mixture was stirred at room temperature for 45 min. H2O (200 ml) was added. The aqueous layer was extracted 3 times with AcOEt. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude residue was taken up in hexane and stirred at rt. Filtration provided [4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol (4.0 g, 87%) as a white solid. MS: m/e=354.0 (M+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18](I)[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[F:24][C:25]([F:64])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:44]=3B3OC(C)(C)C(C)(C)O3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.C>[Pd](Cl)Cl.C(P(CCCC)[C-]1C=CC=C1)CCC.[C-]1(P(CCCC)CCCC)C=CC=C1.[Fe+2]>[C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([C:44]3[CH:45]=[CH:46][C:47]([C:49]([F:52])([F:51])[F:50])=[CH:48][C:43]=3[CH2:42][N:38]3[C@@H:37]([CH3:62])[C@@H:36]([C:28]4[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=[C:26]([C:25]([F:24])([F:63])[F:64])[CH:27]=4)[O:40][C:39]3=[O:41])[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1I
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCCP(CCCC)[c-]1cccc1
Product: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of 2-[4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]-2-oxoethyl acetate (Step A; 33 mg; 0.076 mmol) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Intermediate 9; 68 mg, 0.114 mmol) was treated with 1,1′-bis(di-1-butylphosphino)ferrocene palladium dichloride (˜5 mg) as described earlier. The product was purified by chiral HPLC (ChiralPak IA column, 15% IPA/heptane) to afford 2-{4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidin-1-yl}-2-oxoethyl acetate as a colorless glass. LCMS=779.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.86 (s, 1H), 7.69 (s, 2H), 7.68-7.60 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 6.96-6.91 (m, 1H), 6.72 (dd, J=11.9, 2.1 Hz, 1H), 5.59-5.54 (m, 1H), 4.90 (d, J=15.6 Hz, 1H), 4.80-4.65 (m, 3H), 4.13-4.04 (m, 1H), 3.88-3.72 (m, 2H), 3.78 (s, 3H), 3.21-3.04 (m, 2H), 2.72-2.67 (m, 1H), 2.17 (s, 3H), 1.96-1.83 (m, 2H), 1.70-1.59 (m, 2H), 0.42-0.39 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:39])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(O)(=O)C.[Pd]>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])([OH:39])[CH2:10][N:11]4[CH:15]=[N:14][CH:13]=[N:12]4)=[CH:19][CH:20]=3)[CH2:25][CH2:26]2)=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reaction time: 4 h

Procedure:
The product of part (i) (3.0 g, 5.2 mmole) in acetic acid (50 ml) was hydrogenated over 5% palladium on charcoal (0.3 g) at 25 p.s.i. (172 kPa) for 4 hours. The resulting mixture was filtered, the filtrate concentrated under reduced pressure and the residue partitioned between aqueous sodium carbonate and methylene chloride. The organic phase was separated and the aqueous phase further extracted with methylene chloride. The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to provide a foam. Trituration with petroleum ether (40°-60°) yielded the desired product, m.p. 120° (2.8 g, 98%), which was used without further purification.
Reaction SMILES: C[O:2][C:3]1(OC)[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:15]([C:17]1[C:18]([CH:23]([F:25])[F:24])=[N:19][N:20]([CH3:22])[CH:21]=1)=[O:16].Cl.O>CC(C)=O>[O:2]=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:15]([C:17]1[C:18]([CH:23]([F:25])[F:24])=[N:19][N:20]([CH3:22])[CH:21]=1)=[O:16]
Reactant: COC1(OC)C2CCC1c1c(NC(=O)c3cn(C)nc3C(F)F)cccc12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=O)c(C(F)F)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
An oven-dried Schlenk was charged with compound 4 (100 mg, 0.26 mmol) and dissolved in acetone (1 mL). Hydrochloric acid was added (37%, 2 drops) and the mixture was stirred under nitrogen for 30 minutes at 50° C. GCMS analysis indicated compete conversion of starting material and water was added to mixture (5 mL). Extraction into ethyl acetate (3×5 mL) followed by concentration in vacuo affords compound 5 (quantitative conversion).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][CH2:9][CH2:10][N:11]([C:12](=O)[CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].B.O1CCCC1>O1CCCC1>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CN1CCCC1)N1CCSc2ccc([N+](=O)[O-])cc21
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)N(CCN1CCCC1)CCS2
Temperature: 55 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a stirred solution of 1-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-(pyrrolidin-1-yl)ethanone (750 mg, 2.440 mmol) in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (1M in tetrahydrofuran; 7.32 mL, 7.32 mmol). The resulting mixture was then stirred at 55° C. overnight. The reaction mixture was then cooled to room temperature and quenched carefully via the slow, dropwise addition of methanol (5 mL). The quenched mixture was then stirred at 55° C. overnight. At this time, the reaction was vented to the atmosphere. The mixture was then concentrated and chromatographed on silica gel, eluting with 1:4:5 (2M NH3 in methanol):ethyl acetate:dichloromethane, giving the desired product (654 mg, 91%) as a red oil. 1H NMR (DMSO-d6) δ 7.46 (d, J=2.4 Hz, 1H), 7.36 (dd, J=8.4, 2.1 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 3.69-3.65 (m, 2H), 3.50 (t, J=6.9 Hz, 2H), 3.14-3.10 (m, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.56-2.51 (m, 2H), 1.71-1.66 (m, 4H); ESI-MS (m/z, %): 294 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7].[Br:14]Br>CO.C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)c(N)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.3 %

Procedure:
10.5 Grams (55 mmole) of methyl 3-methoxy-4-aminobenzoate was dissolved in 80 ml methanol, and 3.0 ml bromine (55 mmole) in 20 ml acetic acid was added dropwise at room temperature. The solution was stirred for three hours at room temperature and the solvents were evaporated under reduced pressure. The residue was treated with sodium bicarbonate solution and the product was filtered and air-dried to yield 16.5 grams of methyl 3-bromo-5-methoxy-4-aminobenzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH3:19])[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(C)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(C)cc2C1=O
Yield: 106.2 %

Procedure:
33 mg of methyl 7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are dissolved in 1 cm3 of dioxane at a temperature close to 20° C. 0.3 cm3 of a 1N aqueous solution of sodium hydroxide is added, then the reaction mixture is heated at a temperature close to 60° C. for 1 h. The mixture is then concentrated to dryness under reduced pressure (5 kPa), taken up by 10 cm3 of water and 15 cm3 of ethyl ether. The aqueous phase is decanted, washed with 10 cm3 of ethyl ether, acidified with 0.3 cm3 of a 2N aqueous solution of hydrochloric acid and taken up with 10 cm3 of dichloromethane. The organic phase is extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 33.5 mg of 7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a colorless lacquer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](CCl)=[CH:29][N:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:30]3[CH:29]=[N:28][C:27]([Cl:26])=[CH:32][CH:31]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: ClCc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nc3)c2CC1
Yield: 96.3 %

Procedure:
Use a method similar to General Procedure 7, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2 g, 5.2 mmol) and 2-chloro-5-(chloromethyl)pyridine (843 mg, 5.2 mmol) to give 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.2 g, 95%). MS (ES+) m/z: 439.1 (M+H)+.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][C:5]([O:7]C)=O.[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.Cl>>[CH3:12][N:13]([C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9])[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1
Reactant: CNCCc1c[nH]c2ccccc12
Reactant: COC(=O)CCCC(=O)OC
Agent: Cl
Product: COC(=O)CCCC(=O)N(C)CCc1c[nH]c2ccccc12
Temperature: 150 °C
Yield: 74.8 %

Procedure:
8.0 g of dimethyl glutarate were added to 8.70 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole), and the mixture was heated at 150° C. under reduced pressure for 2 hours. After the reaction was completed, the mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, successively. The washed extract was dried and evaporated under reduced pressure to remove solvent. The residue thus obtained was recrystallized from a mixture of ethyl acetate and n-hexane. 11.3 g of N-methyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. M.p. 101°-102° C. Yield: 70%
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([CH:23]=[CH:24][C:25]=2[F:26])[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([NH:22][S:36]([C:30]3[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])[CH:23]=[CH:24][C:25]=2[F:26])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.357 mL, 2.64 mmol) the title compound of Step A was obtained as a light yellow solid (857 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 7.64-7.72 (m, 1H), 7.49-7.56 (m, 1H), 7.21-7.32 (m, 3H), 6.55 (d, J=5.3 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:23]=[CH:22][C:9]2[NH:10][C:11](=[O:21])[N:12]([C:13]([CH3:20])([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]=2[CH:7]=1)[CH3:4].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[S:35](Cl)(=[O:37])=[O:36].O>C1COCC1.CN(C=O)C>[CH2:3]([O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([S:35]([C:27]3[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:26]=3[O:25][CH3:24])(=[O:36])=[O:37])[C:11](=[O:21])[N:12]([C:13]([CH3:20])([CH3:19])[CH2:14][C:15]([CH3:17])([CH3:16])[CH3:18])[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2[nH]c(=O)n(C(C)(C)CC(C)(C)C)c2c1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(c1)n(C(C)(C)CC(C)(C)C)c(=O)n2S(=O)(=O)c1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
0.2 g of sodium hydride as a 60% dispersion in oil is added in portions to a solution of 1 g of 5-ethoxy-1,3-dihydro-3-(1,1,3,3-tetramethylbutyl)-2H- benzimidazol-2-one in 10 ml of THF and 20 ml of DMF and the mixture is stirred for 30 minutes at RT. 1.2 g of 2-methoxy-4-nitrobenzenesulfonyl chloride are then added and the mixture is stirred for 5 hours at RT. The reaction mixture is poured into 200 ml of water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 1.1 g of the expected product after crystallization from iso ether. M.p.=158° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])([O-])=O.[H][H].C(#N)C>C(O)C.[Pt]>[NH2:1][C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Agent: [Pt]
Solvent: CCO
Solvent: CC#N
Product: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
In 10 ml of ethanol, 1 g (2.88 mmol) of 2-nitro-4,5,3',4'-tetramethoxybenzophenone (prepared according to Example 2) was hydrogenated on 100 mg of platinum/activated carbon (5 percent Pt, moist, H2O content 50 percent) at 40° C. and a hydrogen pressure of 2 bar. After 5 h, the reaction mixture was cooled to room temperature, and 10 ml of acetonitrile was added. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 0.88 g of 2-amino-4,5,3',4'-tetramethoxybenzophenone as a beige solid. The yield of the product was 96 percent of theory.
Reaction SMILES: CN(C=O)C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7].[H-].[Na+].[C:18]1([N:24]=[C:25]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:26]=[CH:27]S(C2C=CC=CC=2)(=O)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:18]1([N:24]=[C:25]([O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:26]=[CH:27][N:9]([C:6](=[O:8])[CH3:7])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=S(=O)(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To DMF (3 ml) solution of acetanilide (0.14 g) was added sodium hydride (60% in oil: 0.043 g) under ice-cooling, and DMF (2 ml) solution of phenyl N-phenyl-3-(phenylsulfonyl)acrylimidate (0.30 g) was added dropwise. It was stirred for two hours under ice-cooling and for one hour at room temperature. Ethyl acetate (100 ml) was added to the reaction mixture and was successively washed with water and aqueous saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain phenyl N-phenyl-3-(N′-acetyl-N′-phenylamino)acrylimidate (0.050 g) as yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4C)c3O2)cc1
Yield: 76.9 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-methylphenyl boronic acid (1.017 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 provided 1.58 g (77%) of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Rf=0.47 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C22H19FO4S.0.2 C4H8O2: C, 66.46; H, 5.30. Found: C, 66.25; H, 4.98.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CN(C)CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), N,N-dimethylglycine hydrochloride (31 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (44 mg). MS found for C28H32F2N6O2 as (M+H)+ 523.5. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 7.33 (2H, d, J=8.8 Hz), 7.26 (1H, m), 7.17 (1H, m), 7.14-7.07 (3H, m), 5.80 (1H, s), 4.68 (1H, m), 4.55 (2H, s), 4.37 (1H, d, J=16.0 Hz), 4.27 (1H, d, J=16.0 Hz), 3.81 (1H, m), 3.27 (1H, m), 2.97 (6H, s), 2.92-2.83 (2H, m), 1.95 (2H, m), 1.71 (2H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=1[Cl:25])[N:5]1[C:9]([CH2:10][CH2:11]OS(C)(=O)=O)=[CH:8][N:7]=[CH:6]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[Cl:25])[N:5]2[CH:6]=[N:7][CH:8]=[C:9]2[CH2:10][CH2:11]1)=[O:26]
Reactant: COC(=O)C(c1ccc(C#N)cc1Cl)n1cncc1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccc(C#N)cc2Cl)CCc2cncn21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The crude (2-chloro-4-cyanophenyl)-[5-(2-methanesulfonyloxyethyl)imidazol-1-yl]-acetic acid methyl ester (2.56 g, 6.45 mmol) is dissolved in dry DMF (50 mL) and to it is added K2CO3 (2.67 g, 19.4 mmol), NaI (2.9 g, 19.4 mmol) and Et3N (2.7 mL, 19.4 mmol). The reaction is stirred at 80° C. for 2 h before being concentrated to dryness. The residue is then diluted with EtOAc and washed with water. The organic layer is dried (Na2SO4) and evaporated to give a crude residue that is purified via flash column chromatography (Acetone/CH2Cl2 1:3) to give 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester as an oil. MS (ESI) m/z 302.2, 304.2 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 2.64-2.76 (m, 2H), 2.97-3.06 (m, 1H), 3.84 (s, 3H), 3.86-3.93 (m, 1H), 6.56 (d, J=8.1 Hz, 1H), 6.87 (s, 1H), 7.50 (obs d, J=8.1 Hz, 1H), 7.52 (s, 1H), 7.73 (s, 1H).