Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:13]1[S:9][C:10]([C:14]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][CH:12]=1
Reactant: N#CC1(c2nccs2)CCCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ncc(Br)s2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
N-Bromosuccinimide (0.33 g, 1.87 mmol) was added to a solution of the product from Step 1 (300 mg, 1.56 mmol) in DMF (5 ml) and the resulting reaction mixture was stirred at room temperature for 2 hrs. 2 aliquots of N-bromosuccinimide (0.33 g, 1.87 mmol) were added over a period of 23 hrs before addition of saturated aqueous Na2S2O3 (10 mL). The mixture was then extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 7% to 60% EtOAc in Hexanes) to afford 1-(5-bromo-1,3-thiazol-2-yl)cyclohexanecarbonitrile (96 mg, 0.35 mmol, 22.7% yield) as a pale yellow oil. MS ESI: [M+]+ m/z 272.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([CH3:12])[C:8](N)=[C:7]([Cl:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[C:1]([C:5]1[CH:11]=[C:10]([CH3:12])[CH:8]=[C:7]([Cl:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(Cl)c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Cl)cc(C(C)(C)C)c1

Procedure:
4-t-Butyl-2-chloro-6-methylaniline (1.97 g) was dissolved in ethanol (50 ml); sulphuric acid (1.88 ml, conc.) was added dropwise and the resulting blue solution was heated at reflux. Sodium nitrite (1.72 g) was added portionwise over 30 min. The resulting mixture was heated at reflux for a further 30 min, then cooled and was poured onto ice-water and extracted with ether (2×50 ml). The ethereal extract was dried (MgSO4) and evaporated and the residue was purified on silica gel using hexane as eluant. This afforded the product as a colourless oil. 1H NMR (360 MHz, CDCl3) δ1.29 (9H, s, (CH3)3), 2.31 (3H, s, CH3), 6.98 (1H, brs, ArH), 7.05 (1H, brs, ArH), 7.15 (1H, brs, ArH). MS (CI-) m/z 181 (M+ -H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:10]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:12]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:36](=O)[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:10]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:12]=[C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(NCc2ccc(C#N)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)CC=O
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2ccc(C#N)cc2)c1

Procedure:
Following the procedure of Example 39, step (a), reaction of 2-[5-(4-Cyano-benzylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester, compound 47a with isovaleraldehyde gave the title compound; Calcd. MW 550.67. Found MH+ 551.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:44][C:45]1[O:46][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:49]=1.ClCC1C=NC(OC)=NC=1>>[F:51][C:50]([F:53])([F:52])[C:47]1[O:46][C:45]([CH2:44][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:49][CH:48]=1
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@@]12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, (3R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 68-70° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.32-7.26 (m, 1H), 7.20 (d, J=7.4 Hz, 1H), 7.10-7.05 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.75-6.74 (m, 1H), 6.45 (s, 1H), 6.42 (s, 2H), 5.12 (d, J=16.2 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.85 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6 Hz, 2H), 3.07-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.4, 161.8, 161.1, 151.9, 141.9, 141.2, 132.5, 128.8, 123.9, 123.7, 120.5, 120.0 (2C), 118.7, 112.6, 112.5, 109.2, 108.7, 93.1, 80.3, 72.3, 57.6, 36.8, 28.9; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH2:17]([N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][CH:3]([O:2][CH3:1])[O:15][CH3:16])[C:13]=2[NH:12][C:11]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(Cc1cccc2[nH]c(=O)[nH]c12)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cc1cccc2c1[nH]c(=O)n2Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
4-(2,2-Dimethoxy-ethyl)-1,3-dihydro-benzoimidazol-2-one (435 mg, 1.96 mmol) was dissolved along with benzyl bromide (335 mg, 1.96 mmol) in 10 mL of anhydrous DMF. Potassium tert-butoxide (1.0 M in THF, 2.2 mL, 2.2 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes and then partitioned between ether and water. The organic phase was washed with brine and dried over Na2SO4. After filtration and removal of solvent under reduced pressure, the crude material was chromatographed to afford 1-benzyl-4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzoimidazol-2-one (100 mg, 16%). 1H NMR (CDCl3) δ 3.00 (2H, d, J=5.0 Hz), 3.40 (6H, s), 4.55 (1H, t, J=5.0 Hz), 6.75 (d, 1H, J=7.5 Hz), 6.84-6.95 (m, 2H), 7.23-7.35 (m, 5H), 8.95 (br s, 1H). 13C(CDCl3) δ 36.9, 44.9, 54.4, 105.6, 107.5, 118.8, 121.7, 124.0, 127.9, 128.0, 129.1, 129.2, 130.8, 136.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[Cl:19])=[CH:6]OCC)[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(O)(C)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[Cl:19])=[CH:6][NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=1)[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Solvent: CC(C)O
Product: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(2-Chloro-4,5-difluorobenzoyl)-3-ethoxy-2-propenoic acid ethyl ester (material from preceding preparation) was mixed with isopropyl alcohol (250 ml) and cooled to 0°. 4-Fluoroaniline (9.33 g, 84.0 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. The precipitate was filtered and washed with isopropyl ether, yielding the title product (11.0 g, 28.7 mmol). Additional product (10.2 g, 26.6 mmol, 73% overall yield for two steps) was obtained from the filtrate, which was concentrated in vacuo and subjected to column chromatography (eluting with chloroform), providing material was was further purified by recrystallization from ether/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH2:5]2.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH:5]2[C:20](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a stirred solution of 0.75 g (3.6 mmole) of 5-chloro-1-acetyl-2-oxindole and 0.96 ml (7.9 mmole) of 4-(N,N-dimethylamino)pyridine in 20 ml of N,N-dimethylformamide, cooled to ca. 0° C, was added a solution of 0.4 ml (3.7 mmole) of 2-thenoyl chloride in 5 ml of N,N-dimethylformamide, dropwise, during a few minutes. The reaction mixture was stirred for 30 minutes at ca. 0° C. and then for 3.5 hours at room temperature, and then it was poured into 500 ml of ice-cold 2N hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried using magnesium sulfate. Evaporation of the dried ethyl acetate solution gave 1.1 g of crude product. The latter was purified by column chromatography using silica gel and eluting with dichloromethane-ethyl acetate mixtures, followed by recrystallization from a small volume of toluene, to give 250 mg of the title compound, m.p. 168°-170° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:28])[CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]2=3)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CCO>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([CH2:12][CH:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[CH:6][CH:7]=3)[OH:28])[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CCOC(=O)c1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C(=O)O)cc2)CCN(C)C1
Temperature: 65 °C
Yield: 80.7 %

Procedure:
To a solution of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoic acid ethyl ester (800 mg, 2.04 mmol) in 5 mL EtOH was added sodium hydroxide (327 mg, 8.17 mmol, in 5 mL water) and heated to 65° C. After complete conversion of starting material (TLC and LCMS), the EtOH and water were removed under reduced pressure. The crude product was passed through HPLC to yield 600 mg of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoic acid. 1H NMR (DMSO, freebase) δ (ppm): 7.79 (d, 2H), 7.29 (s, 1H), 7.17 (d, 2H), 7.09 (s, 1H), 6.88 (d, 1H), 5.5 b(s, 1H), 4.82 (t, 1H), 4.12 (dd, 1H), 4.06 (dd, 1H), 3.44 (s, 2H), 3.16 (s, 2H), 2.71 (d, 1H), 2.56 (m, 2H), 2.36 s (7H). Separation by chiral HPLC provides enantiomers 67a and 67b.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[Cl:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([O:9][C:7]1[CH:6]=[CH:5][C:4]([CH:10]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]3=[O:21])=[C:3]([CH2:1][CH3:2])[CH:8]=1)[CH:32]=[N:31]2
Reactant: CCc1cc(O)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(Oc2cnc3cc(Cl)ccc3n2)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
4-(2-Ethyl-4-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.100 g, 0.34 mmol) is added to a mixture of 2,6-dichloroquinoxaline (0.081 g, 0.41 mmol) and potassium carbonate (0.110 g, 0.69 mmol) in N,N-dimethylformamide (3 ml), and the mixture is heated at 140° C. under microwave irradiation for 40 minutes. The mixture is cooled to room temperature, then acidified by addition of 2M aqueous hydrochloric acid. The mixture is diluted with dichloromethane and passed through a phase separation cartridge. The organic phase is concentrated to around 2 ml, and purified by preparative reverse phase HPLC to give 4-[4-(6-choroquinoxalin-2-yloxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([NH:12][C:13]1C=CC=CC=1O)=[O:11].[C:30](N1C=CN=C1)(N1C=CN=C1)=S.[NH2+]1C2C=CC=CC=2N=N1.F[B-](F)(F)F.CNC>ClCCl.O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:20][C@H:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]([N:12]([CH3:13])[CH3:30])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)N=N[NH2+]2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of methyl N-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (203 mg) and 1,1′-thiocarbonyldiimidazole (100 mg) in dichloromethane (5 ml) was left to stand for 18 hours. Water (10 l) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-, tetrafluoroborate (1-), 3-oxide (TBTU, 321 mg) and a solution of dimethylamine in tetrahydrofuran (0.5 ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5 g, silica) eluting with a gradient (8:1 to 1:2 cyclohexane:ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100 mg).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([F:18])=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15]C)[C:11]([F:17])=[CH:10]2)=[CH2:4].[I-].[Na+]>C(#N)C>[F:18][C:6]1[CH:7]=[N:8][C:9]2[CH:10]=[C:11]([F:17])[C:12](=[O:15])[N:13]3[CH2:2][C:3](=[CH2:4])[C:5]=1[C:14]=23
Reactant: C=C(CCl)c1c(F)cnc2cc(F)c(OC)nc12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C=C1Cn2c(=O)c(F)cc3ncc(F)c1c32

Procedure:
A mixture of 8-[1-(chloromethyl)ethenyl]-3,7-difluoro-2-(methyloxy)-1,5-naphthyridine (320 mg, 1.18 mmol) and sodium iodide (885 mg) in acetonitrile (20 ml) was heated to reflux for 20 hours. The cooled mixture was evaporated then diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica eluting with a gradient of 0-100% ethyl acetate in hexane affording product (168 mg, 65%).
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]([CH2:18][CH:19](OCC)OCC)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]=1[CH3:26].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:5][C:6]1[C:11]([CH3:12])=[C:10]2[C:9](=[CH:8][C:7]=1[CH3:26])[N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:18]=[CH:19]2
Reactant: CCOC(CN(c1cc(C)c(Br)c(C)c1)S(C)(=O)=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c(ccn2S(C)(=O)=O)c(C)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A 1 M solution of titanium(IV) chloride in dichloroethane (5.3 ml, 5.3 mmol) was added to a solution of N-(4-bromo-3,5-dimethyl-phenyl)-N-(2,2-diethoxy-ethyl)-methanesulfonamide (2.09 g, 5.3 mmol) in toluene (17 ml) at room temperature, and the mixture was heated with stirring at 100° C. for two hours. An aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-bromo-4,6-dimethyl-1-methanesulfonyl-indole (1.28 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[C:16]([Cl:37])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(OC)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(3-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 428 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)c(N)s2)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid (Intermediate 133) gave 292. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.82 (s, 1H), 7.44 (s, 2H), 7.26-7.17 (m, 2H), 4.86 (dd, J=10.2, 3.8 Hz, 1H), 4.54-4.36 (m, 1H), 4.34-4.18 (m, 1H), 4.15-3.96 (m, 1H), 3.77 (s, 3H), 2.35 (s, 3H), 2.14-2.03 (m, 1H), 1.88-1.65 (m, 4H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([Cl:32])[CH:31]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:28]2[CH:27]=[C:26]([Cl:25])[CH:31]=[C:30]([Cl:32])[CH:29]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2cc(Cl)cc(Cl)c2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 3,5-dichlorophenylboronic acid, followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][OH:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[CH2:33][OH:34])[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: OC[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCC[C@H]2CO)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 32.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (S)-pyrrolidin-2-ylmethanol hydrochloride (0.21 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.25 g, 32%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[F:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O.C(OCC)(=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[F:22][C:23]1[CH:28]=[C:27]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Fc1cccc(I)c1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: BrCCBr
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.8 %

Procedure:
A solution of 1,2-dibromoethane (0.30 g) in anhydrous DMF (25 ml) was stirred with zinc dust (1.39 g) at 70° C. for 10 minutes then cooled to room temperature and chlorotrimethylsilane was (0.155 g) added. The resultant mixture was stirred at room temperature for 45 minutes. tert-Butyl 3-iodoazetidine-1-carboxylate (5 g) added and stirring was continued at 40° C. for 45 minutes then a solution of 3-fluoroiodobenzene (4.08 g), tris(dibenzylideneacetone)dipalladium(0) (0.325 g) and tris(2-furyl)phosphine (0.165 g) in DMF (15 mL) was added and the mixture was stirred at 70° C. for 3 hours. After cooling, the mixture was diluted with water and ethyl acetate and filtered through celite. The organic layer was washed twice with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-10%. The crude product was further purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane with a gradient of 0-100% to give tert-butyl 3-(3-fluorophenyl)azetidine-1-carboxylate (2.52 g) as a colourless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]1[CH2:9][CH:8]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:14][CH:13]=1)=[O:11])[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>>[CH2:1]([N:3]([CH2:6][CH:7]1[CH2:9][CH:8]1[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:16][CH:17]=1)[OH:11])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC1CC1C(=O)c1ccc(-n2ccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)CC1CC1C(O)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Example 27, react [2-[(diethylamino)methyl]cyclopropyl][4-(1H-imidazol-1-yl)phenyl]-methanone with sodium borohydride to obtain the title compound.