Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([OH:14])=[O:13]>C(O)(=O)C.C1CCCCC1>[Br:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: Cc1cccc(C)c1CC(=O)O
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(Br)c(C)c1CC(=O)O
Temperature: 45 °C
Reaction time: 16 h

Procedure:
At 45° C., a solution of 8.5 kg [53.2 mol] of bromine in 10 l of glacial acetic acid is added dropwise to a solution of 6.86 kg [40.45 mol] of 2,6-dimethylphenylacetic acid in 401 of glacial acetic acid. The reaction mixture is then stirred at 45° C. for another 16 hours and concentrated on a rotary evaporator. The solid obtained is stirred in 10 l of cyclohexane at room temperature. After filtration, the residue is washed a little at a time with 10 l of cyclohexane and then dried. This gives 8.43 kg of a solid.
Reaction SMILES: [H-].[Na+].CN([CH:6]=[O:7])C.CO.[Cl:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3>O>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH3:6])[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3
Reactant: CN(C)C=O
Reactant: Cn1c(=O)c(-c2ccc(F)cc2Cl)cc2c3ccccc3n(C)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc3c4ccccc4n(C)c3n(C)c2=O)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
3.25 g (81.1 mmol) of 60% NaH are added to 300 ml of DMF and 9.6 ml of MeOH. The mixture is left to stir for 5 minutes, and then 9.22 g (27.0 mmol) of compound A 3-(2-chloro-4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are added. The mixture is stirred at ambient temperature and then, as soon as no more gas is being given off, is heated at 80° C. for 16 h. The reaction medium is left to cool and poured into H2O, the yellow precipitate is filtered off and washed with H2O, the residue is taken up in MeOH and the product is concentrated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-bromophenyl)ethanone (8 g, 40.2 mmol) in 150 mL of THF was added MeMgCl (3.0 M in THF, 40 mL, 120 mmol) at −78° C. The reaction was stirred at rt overnight, and quenched with 150 mL of aqueous NH4Cl. The product was extracted with 250 mL of EtOAc, and the extracts were dried over anhydrous MgSO4, and concentrated to give 2-(4-bromophenyl)propan-2-ol, which was used without further purification.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.ClC1C=CC(N)=CC=1C(F)(F)F.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[S:44])=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46]>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:44]2)=[CH:38][C:37]=1[C:45]([F:46])([F:47])[F:48]
Reactant: CCC(C)[C@H](N)CO
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc(Cl)c(C(F)(F)F)c2)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Chloro-3-(trifluoromethyl)aniline was converted to 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate according to Method A2a, Step 3 4-Chloro-3-(trifluoromethyl)phenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24]O)=[CH:21][C:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:19]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 2-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine to give (6-{2-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1.[CH3:26][O-:27].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:27][CH3:26])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3cccc(CO)c3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(CO)c3)c2n1
Temperature: 70 °C
Yield: 76.6 %

Procedure:
To a solution of Compound (6) (1.53 g, 3.74 mmol) in methanol (40 mL) was slowly added sodium methoxide (4.04 g, 74.85 mmol). The reaction mixture was heated to 70° C. for 5 hours, at which time Dowex (H+) resin was added to quench any remaining methoxide. The resin was filtered off and the solvent was evaporated. Salts were removed by partition between water and dichloromethane, and the combined organic layers were dried over magnesium sulfate and evaporated to dryness giving 1.03 g (76%) of Compound (7) as a white solid, which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.39 (s, 3H), 3.73 (t, J=4.8, 9.6 Hz, 2H), 4.12 (s, 3H), 4.45 (t, J=4.5, 9.3 Hz, 2H), 4.56 (s, 2H), 5.12 (s, 2H), 7.28 (m, 4H). LCMS: m/z for C17H21N5O4++H observed 360.1 at 1.87 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:13]1[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=[C:15]([S:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=2[F:52])[N:14]=1>>[C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:13]2[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:16]=[C:15]([S:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[N:14]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: N#Cc1ccc(S(N)(=O)=O)o1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 5-cyanofuran-2-sulfonamide (the product of step i) (0.29 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product of Example 13, step ii) (0.15 g) according to the procedure outlined in Example 1, step iv). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:4 to 2:3 gradient) to give the subtitle compound as a pale yellow solid. Yield: 0.25 g
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19]O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.[C:30]1(=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[NH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([C:2]([F:29])([F:28])[F:1])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][N:31]2[C:32](=[O:39])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]2=[O:40])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)ethanol (200 mg, 0.48 mmol), isoindoline-1,3-dione (105 mg, 0.71 mmol), and triphenylphosphine (187 mg, 0.71 mmol) in tetrahydrofuran (5 mL) at 0° C. was added diethyl azodicarboxylate (0.112 mL, 0.71 mmol). The ice bath was removed and stirring continued for 1 h. Clean, complete conversion to product was observed. The reaction was quenched by addition of saturated ammonium chloride, and extracted with ethyl acetate (2×). The organics were washed with water, then saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (8% EtOAc/Hex-->12% EtOAc/Hex) gave 255 mg (98%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.73 (s, 1H), 7.67 (m, 2H), 7.63 (s, 2H), 7.61 (m, 2H), 7.00-7.15 (m, 4H), 5.16 (qAB, JAB=12.2 Hz, 2H), 4.60 (s, 2H), 3.77 (m, 1H), 3.68 (m, 1H), 3.63 (s, 2H), 2.47 (m, 1H), 2.30 (ddd, J=14.4, 7.3, 4.9 Hz, 1H); 13C-NMR (CDCl3, 126 MHz) δ 168.1, 141.2, 140.6, 140.0, 133.7, 132.2, 131.7 (q, J=33.6 Hz), 128.0, 127.4, 127.2, 123.4 (q, J=273 Hz), 122.9, 121.5, 121.4, 121.2, 88.9, 76.8, 73.0, 72.0, 33.6, 33.5. Mass spec.: 550.20 (MH)+.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.Br[CH2:9][CH:10]([F:12])[F:11]>>[F:11][CH:10]([F:12])[CH2:9][N:4]1[CH:3]=[C:2]([I:1])[N:6]=[C:5]1[CH3:7]
Reactant: FC(F)CBr
Reactant: Cc1ncc(I)[nH]1
Product: Cc1nc(I)cn1CC(F)F

Procedure:
The title compound, MS: m/e=273.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-methyl-1H-imidazole and 2-bromo-1,1-difluoroethane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:13]([CH3:16])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CCN(CC)CC>C(Cl)Cl>[CH:26]1([NH:31][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
To a mixture of (2R,3R)-2-(tert-butoxycarbonylamino)-3-methylpentanoic acid (0.5 g, 2.162 mmol, HATU (0.986 g, 2.59 mmol) and cyclopentanamine (0.427 mL, 4.32 mmol) in DCM (10 mL) was added Et3N (0.603 mL, 4.32 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound (0.56 g, 87%). 1H NMR (400 MHz, CDCl3) δ 0.82-0.89 (m, 3 H) 0.92 (t, J=7.45 Hz, 3 H) 1.32-1.41 (m, 6 H) 1.44 (s, 9 H) 1.55-1.77 (m, 3 H) 1.84-2.04 (m, 2 H) 2.99 (d, J=4.29 Hz, 1 H) 3.96 (dd, J=8.72, 5.43 Hz, 1 H) 4.21 (dt, J=13.89, 6.95 Hz, 1 H) 5.02 (br. s., 1 H) 5.93 (br. s., 1 H).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (8.1 g, 50 mmol) in THF (20 mL) at 10° C. was added a 1 M solution of 4-fluorophenyl magnesium bromide in THF (65 mL, 65 mmol). The resulting mixture was stirred at room temperature for 2 hours before quenching with saturated NH4Cl solution. The solution was extracted with EtOAc 3 times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was taken up in toluene (80 mL). To it was added p-toluenesulfonic acid monohydrate (80 mg). The mixture was stirred at reflux with removal of water using a Dean-Stark trap for 2 hours. The resulting solution was washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5%, 10% and then 15% EtOAc in hexanes provided the title compound (8.8 g, 75%) as a solid. MS calculated (M+H)+235. Found 235.
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[C:35]([F:36])=[CH:34][CH:33]=[C:32]([NH2:37])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])(=O)C.Cl.[OH-].[Na+].O>O1CCOCC1>[NH2:37][C:32]1[C:28]2[C:29](=[O:31])[CH:30]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:4][CH2:5][CH2:6][CH2:7][N:8]4[C:9](=[O:18])[C:10]5=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]5[C:12]4=[O:13])=[CH:24][CH:23]=3)[O:26][C:27]=2[C:35]([F:36])=[CH:34][CH:33]=1
Reactant: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)ccc(F)c3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Yield: 79.9 %

Procedure:
5.78 g of Compound 18 was dissolved in 90 ml of dioxane, 60 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 4 hours. The reaction solution was cooled on ice and adjusted to pH 7 by addition of a 10N aqueous solution of sodium hydroxide thereto, water was further added, and the precipitated crystals were collected by filtration to give 4.23 g (80%) of Compound 19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:31][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=3)[CH:14]([OH:15])[CH3:31])[CH2:10]2)=[CH:29][CH:28]=1
Reactant: O=CC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: C[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 805 mg (1.81 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetaldehyde in 20 mL of THF was added slowly a solution of 1.33 mL (4.0 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h and 3 g of sodium sulfate decahydrate was added to quench the reaction, followed by stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-1-(3,5-difluorophenyl)propan-2-ol as a white solid. Mass Spectrum m/e=460 (M+1 35Cl, 35Cl) and 462 (M+1 35Cl, 37Cl).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1)[C:5]([NH2:7])=[O:6].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>S1(CCCC1)(=O)=O>[OH:14][CH:13]([CH2:15][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[I:1]
Reactant: NC(=O)c1ccc(OCC2CO2)c(I)c1
Reactant: CC(C)(C)N
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)NCC(O)COc1ccc(C(N)=O)cc1I
Yield: 102 %

Procedure:
A solution of 3.75 g (0.01 mole) of 3-iodo-4-(oxiranylmethoxy)benzamide and 10.5 ml (0.1 mole) of t-butylamine in 7 ml of sulfolane was heated at 90° C. in an autoclave. After 2 hr the vessel was cooled and the t-butylamine was evaporated in vacuo. The residue was crystallized from CH2Cl2 /CH3CN to give 4.0 g (100% yield) of 4-[2-hydroxy-3-[(1,1-dimethylethyl)amino]propoxy]-3-iodobenzamide as a white crystalline solid, mp 111°-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)C>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CCCBr
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Yield: 63.7 %

Procedure:
30.0 g of 2-aminobiphenyl, 23.4 g of ethyl diisopropylamine and 35.4 g of ethyl 4-bromobutyrate are heated together to 150° for 3 hours while stirring. After cooling, the reaction product is stirred with diethyl ether, the precipitated salt is filtered off, and the residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 32.0 g (63.7% of theory) of ethyl 4-(biphenyl-2-yl)aminobutyrate, MP 60° to 62°.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13]2[N:17]=[C:16]([SH:18])[S:15][N:14]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>C(O)C.C(Cl)Cl>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13]2[N:17]=[C:16]([S:18][CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24])[S:15][N:14]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: FC(F)=C(F)CCBr
Reactant: O=[N+]([O-])c1ccc(CSc2nsc(S)n2)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CSc2nsc(SCCC(F)=C(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of 0.25 gram (0.011 mole) of sodium in 35 ml of ethanol was stirred and 2.7 grams (0.0095 mole) of 3-(4-nitrophenylmethylthio)-5-mercapto-1,2,4-thiadiazole was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for one hour. The ethanol solvent was removed under reduced pressure. The residue was dissolved in 35 ml of methyl ethyl ketone and 1.6 grams (0.0085 mole) of 4-bromo-1,1,2-trifluoro-1-butene was added. Upon completion of addition the reaction mixture was stirred for 16 hours, then was concentrated under reduced pressure to a residue. The residue was dissolved in 50 ml of toluene and washed with 25 ml of water, two 25 ml portions of aqueous 5% sodium hydroxide solution, and 25 ml of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a residual oil. The oil was dissolved in methylene chloride and passed through a column of silica gel. The eluate was concentrated under reduced pressure to yield 2.1 grams of 3-(4-nitrophenylmethylthio)-5-(3,4,4-trifluoro-3-butenylthio)-1,2,4-thiadiazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:38]([CH2:37][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:19])=[O:20])[CH:16]=[CH:17][C:9]1=2)#[N:39]
Reactant: N#CCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC#N)cc1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
To a solution of 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (From Example 256, Step 3; 550 mg, 1.080 mmol) and 2-bromoacetonitrile (194 mg, 1.62 mmol) in DMF (10 mL) was added potassium carbonate (447 mg, 3.24 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (3×50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-30% ethyl acetate in hexane) to yield 4-(2-(cyanomethoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (200 mg, 33.8%). MS (ESI, positive ion) m/z; 549.1 (M+1)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=1.[C:28]1([C@@H:34]([NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:27][C:23]1[N:22]=[C:21](/[CH:39]=[CH:38]/[C:37]([NH:36][C@H:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:35])=[O:40])[CH:26]=[CH:25][CH:24]=1
Reactant: C=CC(=O)N[C@@H](C)c1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)/C=C/c1cccc(Br)n1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To the solution of triphenylphosphine (0.496 mmol) in DMF (10 mL), a palladium acetate (0.245 mmol) was added at room temperature under argon atmosphere. The mixture was stirred for 5 min then 2,6-dibromopyridine (12.7 mmol) followed by N-((S)-1-phenylethyl)acrylamide (14.0 mmol) and triethylamine (35.9 mmol) were added and the reaction mixture was stirred at 140° C. for 7 hr. The majority of the solvent was removed under diminished pressure. Diluted HCl was added and the product was extracted with ethyl acetate. Organic layers were combined, washed with brine, dried over sodium sulfate. Drying agent and solvent was removed and product was purified by column chromatography using hexanes and hexanes:ethyl acetate 2:1 as eluents, to give pure product with a good yield.