Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])[CH3:12]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][C:11]([OH:15])([CH3:12])[C:13]#[C:14][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(O)C#Cc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
4-Bromobenzaldehyde (3.0 g, 16 mmol), Pd(PPh3)2Cl2 (110 mg, 0.170 mmol) and CuI (16 mg, 0.07 mmol) were placed in a Schlenk flask. The flask was then evacuated and purged with argon (3 times) on the Schlenk line. Then freshly distilled and degassed TEA (32 mL) was added, and after purging with argon, 2-methyl-3-butyn-2-ol (1.90 mL, 19.4 mmol) was added. The reaction mixture was stirred for 2 h at 40° C. (The progress of the reaction was monitored by GC-MS). The reaction mixture was evaporated to dryness and then chromatographed (silica, CH2Cl2). Bulb-to-bulb distillation (93-95° C., 0.001 mm Hg) gave a pale yellowish oil (2.90 g, 95%). 1H NMR (CDCl3) δ 1.61 (s, 6H), 2.23 (brs, 1H), 7.52 (AB/2, J=8.1 Hz, 2H), 7.79 (AB/2, J=8.1 Hz, 2H), 9.02 (s, 1H); 13C NMR δ 31.9, 66.1, 81.9, 98.8, 129.8, 130.1, 132.7, 135.9, 192.3; IR (film) v (cm−1) 790.4, 830.1, 906.3, 963.4, 1014.3, 1046.1, 1165.9, 1207.0, 1273.4, 1303.0, 1373.0, 1457.6, 1563.8, 1603.6, 1700.0, 2228.1, 2735.0, 2837.8, 2934.1, 2982.2, 3413.3; MS (EI+) m/z 188 (M+, 35%), 173 (100%), 159 (10%); EI-MS obsd 188.0835, calcd exact mass 188.0837 (C12H12O2).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:4]3[C:5](=[O:16])[C:6]4[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:17])=[N:24][C:23]=2[CH:25]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: Clc1ccc2sc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(Cl)ccc3s1)c(=O)n2C
Yield: 96.1 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (297 mg, 1 mmol) was dissolved in N,N-dimethylformamide (8 ml). 2-bromomethyl-5-chloro-1,3-benzothiazole (263 mg, 1 mmol) and potassium carbonate (213 mg, 1.5 mmol) were added to give a reaction mixture. The reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 3b (460 mg, light yellow solid), yield: 96%.
Reaction SMILES: [CH3:1][N:2](C)[C:3](Cl)=O.[CH2:7]([NH:13][C:14](=O)[CH3:15])[CH2:8][CH2:9][CH2:10]CC.[OH-].[Na+].C(=O)([O-])[O-].[Ca+2]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:3])[C:14](=[N:13][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:15]
Reactant: CN(C)C(=O)Cl
Reactant: CCCCCCNC(C)=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN=C(C)N(C)C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
Dimethylcarbamyl chloride (9.35 g, 86.9 mmol) was slowly added to a solution of N-hexyl acetamide (10.0 g, 86.9 mmol) in 10 mL of dry toluene. After being refluxed under a nitrogen atmosphere for 16 h, the volatile materials were removed on a rotary evaporator and then in vacuo for 2 h at room temperature. The residue was dissolved in 30 mL dichloromethane and the solution was stirred vigorously with a solution of 3.48 g (86.9 mmol) of sodium hydroxide in 40 mL water for 30 min. Calcium carbonate (3.48 g) was added to the mixture and it was stirred another 30 min. The organic phase was separated and the aqueous phase was washed with dichloromethane (3×25 mL). The combined organic phases were dried over anhydrous calcium carbonate. The volatile materials were evaporated on a rotary evaporator. The residue was distilled, bp 28-30° C./0.25 Torr (lit. bp 69-71° C./13 Torr (see Haug, E. et al. Synthesis, 1983, 35-37)), to yield 4.0 g (32%) of product, 98% pure (GC). IR (neat) 2956, 2929, 286 (C—H), 1629 (N═C) cm−1. 1H NMR 3.17 (t, 2H, JHH 7.2 Hz, —CH2—N═), 2.86 (s, 6H, —N—(CH3)2); 1.87 (s, 3H, —N═C(CH3)—N); 1.5 (m, 2H, —CH2—CH2—N═); 1.25- 1.4 (m, 6H, CH3—(CH2)3—); 0.88 (t, 3H, JHH 7.2 Hz, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:10][CH2:11][OH:12].C(N(C(C)C)C(C)C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:12][CH2:11][CH2:10][CH2:9][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)c1ccccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCOS(C)(=O)=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a solution of (S)-tert-butyl 1-(2-bromophenyl)-4-hydroxybutylcarbamate (compound 5; 59.4 mmol, 20.44 g) in dry methylene chloride (500 mL) cooled in an ice bath was added N-ethyldiisopropylamine (119 mmol, 15.35 g) followed by the slow addition of methane sulfonyl chloride (60.0 mmol, 6.87 g) under nitrogen maintaining the reaction temperature below 5° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and left to stir for two days. The reaction mixture was evaporated at 45° C. under vacuum and residue taken up in methylene chloride (500 mL) washed with 0.5% citric acid, dried over magnesium sulfate with activated charcoal, filtered through a bed of dicalite and evaporated to give a slightly oily solid which was triturated with heptane to give (S)-4-(2-bromophenyl)-4-(tert-butoxycarbonylamino)butyl methanesulfonate 23.25 g) as a pale brown solid, MS (ES): m/z [M+H]+ 422 and 424.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(=O)N)[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[OH-].[Na+].C[N:53]1CCCC1=O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:33])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:53])[CH:24]=3)=[CH:18][C:17]=2[F:32])[CH2:12][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Temperature: 25 °C

Procedure:
1-[4-(2-Carbamoylpyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (17.9 g) was dissolved in N-methyl-2-pyrrolidone (125 ml) at room temperature, and water (7.2 ml) was added. Iodobenzene diacetate (14.1 g) was added with stirring at room temperature, followed by stirring for 4 hours and 7 minutes. Ethyl acetate (268 ml) and a 1N aqueous solution of sodium hydroxide (179 ml) were added to the reaction mixture, and the layers were separated. The organic layer was washed with a 5% aqueous solution of sodium chloride (179 ml) three times and water (179 ml) once, dried over magnesium sulfate, filtered, and concentrated. Toluene (72 ml) was added to the resultant crystals, and the mixture was heated and stirred at 90° C. After confirming the crystals were dissolved, the mixture was allowed to cool down to room temperature. The precipitated crystals were collected by filtration, washed with toluene (18 ml), and dried under reduced pressure at 50° C. for 4 hours to give the title compound (11.9 g) as pale orange crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I.[NH4+].[Cl-]>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:16])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a solution of ethyl 4-bromophenylacetate (2 g, 8.23 mmol) in anhydrous DMF (20 ml) was carefully added NaH (60% in mineral oil, 0.494 g, 12.34 mmol) at 0° C. (ice bath). The resulting slurry was stirred at 0° C. for 30 min, then MeI (0.643 ml, 10.28 mmol) was added and the reaction mixture was allowed to warm to RT and further stirred for 1 h. A saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with AcOEt (2×). The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/AcOEt 99:1 to 8:2) to yield the title compound (777.8 mg, 3.03 mmol, 37% yield) as a colorless oil. TLC: RF=0.64 (heptane/AcOEt 3:1); HPLC: AtRet=2.60 min; 1H NMR (400 MHz, DMSO-d6): 1.13 (t, J=7.1, 3H), 1.37 (d, J=7.1, 3H), 3.79 (q, J=7.1, 1H), 3.98-4.12 (m, 2H), 7.22-7.28 (m, 2H), 7.49-7.56 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[OH:41][C@@H:42]([C:46]([CH3:49])([CH3:48])[CH3:47])C(O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](=[O:15])[C@@H:42]([OH:41])[C:46]([CH3:49])([CH3:48])[CH3:47])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](O)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 113 mg, 0.316 mmol, 1 equiv) in a 1:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via toluene azeotrope (1×10 mL), then dissolved in DMF (4 mL). Triethylamine (0.176 mL, 1.27 mmol, 4.00 equiv), (2S)-2-hydroxy-3,3-dimethylbutanoic acid (84 mg, 0.632 mmol, 2.00 equiv), and PYBOP (329 mg, 0.632 mmol, 2.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 24 hours. Additional triethylamine (0.176 mL, 1.27 mmol, 4.00 equiv), (2S)-2-hydroxy-3,3-dimethylbutanoic acid (84 mg, 0.632 mmol, 2.00 equiv), and PYBOP (329 mg, 0.632 mmol, 2.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 20 hours. The reaction mixture was partitioned between water (70 mL) and ethyl acetate (2×55 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide (2S)-1-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-3,3-dimethyl-1-oxobutan-2-ol (22-1) as a white solid. 1H NMR (500 MHz, CDCl3) rotamers: δ 7.43-7.02 (m, 8H), 6.42 (m, 1H), 5.93 (m, 1H), 5.01-4.82 (m, 2H), 4.16 (major rotamer, s, 1H), 3.85 (minor rotamer, s, 1H), 1.00 (minor, s, 9H), 0.92 (major, s, 9H). LRMS m/z (M+H) 372.0 found, 372.2 required.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([CH3:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].[OH-].[Li+].Cl>CO.O>[CH2:41]([O:40][C:38]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([CH3:29])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)ccc1C1CC(=O)NS1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl (2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylphenyl]propanoate trifluoroacetate (286 mg, 0.649 mmol) in methanol (7.0 mL) was treated with triethylamine (362 μL, 2.60 mmol) and cooled to 0° C. Benzyl chloroformate (116 μL, 0.812 mmol) was added and the solution stirred for 2 h. 2 M lithium hydroxide in water (0.81 mL) was added and the solution stirred for an additional 1 h. The reaction soluiton was acidified with 1 N HCl and extracted with ethyl acetate. The crude product was used in the next step without purification. MF=C21H22N2O7S; LCMS found for C21H23N2O7S (M+H)+: m/z=447.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])#[N:2].S(=O)(=O)(O)[OH:22]>>[CH3:11][N:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1[S:6][N:5]=[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[C:1]([NH2:2])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCSc1nsc(NC(=O)N(C)C)c1C#N
Product: CCCCCCSc1nsc(NC(=O)N(C)C)c1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A mixture of 3-(4-cyano-3-hexylsulfanyl-isothiazol-5-yl)-1,1-dimethyl-urea (0.09 g, 0.29 mmol) and concentrated sulfuric acid (0.18 mL) was stirred at ambient temperature for 1.5 hours. The mixture was diluted with ice water, extracted three times into ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo affording 0.076 g (78%) of 5-(3,3-dimethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acid amide as a colorless solid: 1H NMR (300 MHz, acetone-d6) δ7.08 (bs, 2H), 3.20 (t, 2H, J=7.2 Hz), 3.02 (s, 6H), 1.63 (p, 2H, J=7.2 Hz), 1.35 (m, 2H), 1.23 (m, 4H), 0.78 (t, 3H, J=6.9 Hz) ppm; MS (APCl, m/z): 331 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]3[O:30][CH2:29][C@H:24]([S:25]C(=O)C)[CH2:23]3)=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].CO>C(OCC)(=O)C.CCCCCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([C@@H:22]3[O:30][CH2:29][C@H:24]([SH:25])[CH2:23]3)=[O:21])[CH2:18][CH2:19]2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1CO[C@@H](C(=O)N2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@H]2C[C@@H](S)CO2)CC1
Yield: 41.4 %

Procedure:
The title compound is prepared by the procedure of Example 153 using 0.230 g of product from Example 157, 0.29 ml of 4N sodium hydroxide and 1.7 ml of methyl alcohol to give 0.086 g of the desired product after chromatography (silica gel: 10-100% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C@@H:15](/[CH:16]=[CH:17]/[C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C:12]1=[O:25])[CH3:2].[BH4-].[Na+].Cl.C(OCC)(=O)C>C(O)C.CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C:12](=[O:25])[CH2:13][CH2:14][C@@H:15]1/[CH:16]=[CH:17]/[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCC(O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Reaction time: 7 h

Procedure:
A solution of {(Z)-4-[(R)-2-oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (0.7 g, 1.97 mmol) in 15 mL of ethanol was stirred at 0° C., and 0.082 g NaBH4 was added. The reaction was allowed to come to room temperature and stirred for 7 hours, followed by addition of a solution of hydrochloric acid in methanol (2 M, 1-2 mL) and extraction with ethyl acetate. The organic phase was dried, concentrated, purified via chromatography to yield {(Z)-4-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester, and taken directly on to the next step.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21]OS(C)(=O)=O)[N:19]=2)=[CH:11][CH:10]=1.ClCCl>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21][N:3]3[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]3)[N:19]=2)=[CH:13][CH:14]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: CC1CCCCN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Temperature: 60 °C
Yield: 70.2 %

Procedure:
Add 2-methyl piperidine (0.871 g, 8.77 mmol) to a solution of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (0.316 g, 0.877 mmol) in tetrahydrofuran (5 mL) in a sealed tube, and heat at 60° C. overnight. Cool to room temperature and add dichloromethane. Wash the crude organic material with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give (+/−)-1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.215 g, 67%): MS (m/e): 363 (M+1).
Reaction SMILES: [C:1]([C:3]1([NH:28][C:29](=[O:47])[CH:30]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:31][C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:7][CH2:6][N:5]([CH2:8]C2C3C(=CC=CC=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)[CH2:4]1)#[N:2].[NH4+:48].[Cl-]>CO>[C:1]([C:3]1([NH:28][C:29](=[O:47])[CH:30]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:31][C:32]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:30]2[NH:48][C:42]3[C:41]([CH:40]=2)=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:4]1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCC(C#N)(NC(=O)C(CC(=O)N4CCOCC4)CC4CCCCC4)C3)c3ccccc32)cc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CO
Product: N#CC1(NC(=O)C(CC(=O)N2CCOCC2)CC2CCCCC2)CCN(Cc2cc3ccccc3[nH]2)C1
Yield: 76 %

Procedure:
A suspension of N-{3-cyano-1-[1-(toluene-4-sulfonyl)-1H-indole-3-ylmethyl]-pyrrolidin-3-yl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide (0.052 g, 0.079 mmol) and Mg (powder) (0.038 g, 1.6 mmol) in MeOH (5 mL) was sonicated at room temperature reaction was monitored by MS. When completed, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated to provide the title compound in 76% yield. The compound was recrystallized from Et2O/hexanes. 1H NMR (CDC13) 8.1 (1H, s), 7.71-7.69 (1H, m), 7.39-7.37(1H, m), 7.25-7.15 (3H, m), 6.9 (1H, s), 4.0-3.8 (2H, m), 3.7-3.3 (1H, m), 3.2-3.1 (1H, m), 3.0-2.5 (3H, m), 2.3-2.15 (2H, m), 1.8-1.4 (5H, m), 1.35-1.03 (5H, m), 0.95-0.78 (3H,m). MS, m/z 506=M+1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].[CH3:23][Si:24]([CH3:41])([CH3:40])[C:25]#[C:26][Sn](CCCC)(CCCC)CCCC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:26]#[C:25][Si:24]([CH3:41])([CH3:40])[CH3:23])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C#C[Si](C)(C)C
Temperature: 110 °C
Yield: 79.4 %

Procedure:
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester (1.0 g, 2.56 mmol), trimethyl((tributylstannyl)ethynyl)silane (1.98 g, 5.12 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.256 mmol) were combined in 1,2-dichloroethane (10 mL) and heated in a CEM microwave reactor at 110° C. for 15 min. The cooled reaction mixture was concentrated under vacuum then purified by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient). A second purification by flash chromatography on silica gel (hexane/ethyl acetate gradient) yielded the title compound (0.829 g, 79% yield): mp 126-128° C.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[F:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:53][C:24]([CH3:52])([CH3:23])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([O:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[C:55]([F:54])[CH:56]=1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: Fc1cc(Br)ccc1Oc1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(Oc2ccccc2)c(F)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 94.4 %

Procedure:
A mixture of palladium acetate (20 mg, 0.08 mmol) and tri-(2-methylphenyl)phosphine (50 mg, 016 mmol) was added to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (Preparation 2)(700 mg, 1.63 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10)(479 mg, 1.79 mmol), and triethylamine (340 μL, 2.43 mmol) in anhydrous acetonitrile (3 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 14 h. Additional palladium acetate (20 mg, 0.08 mmol) and tri-(2-methylphenyl)phosphine (50 mg, 016 mmol) was added and the mixture was heated for a further 9 h. After being cooled, the mixture was poured into ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (2×50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate=9:1) to give mainly tert-butyl (3R,5E)-3-({[(1s)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino }carbonyl)-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate as a colourless oil (949 mg). 1H nmr suggested that two alkene isomers, the (5Z) and (4E), together with the alkene starting material (10%) were also present. The mixture of alkenes was taken onto the next step (see b, below).