Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[C:16]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:17]2=[N:18][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:20][C:17]3=[N:18][CH:19]=[C:14]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:1]([OH:3])=[O:2])[CH:15]=[C:16]3[CH:22]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Temperature: 95 °C
Yield: 29.8 %

Procedure:
3-Carboxyphenylboronic acid (700 mg, 4.22 mmol), 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (750 mg, 2.57 mmol), Pd(Ph3P)4 (30 mg, 0.026 mmol), and Cs2CO3 (1.25 g, 3.84 mmol) were combined in dioxane (20 mL) and water (4 mL). The mixture was evacuated/backfilled with nitrogen (3×). The reaction was heated to 95° C. under N2 (g) overnight. The mixture was partitioned between EtOAc and 1 N HCl. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a brown solid which was triturated with Et2O to give the expected product 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (255 mg, 30% yield) consistent by LCMS. LC-MS retention time: 1.83 min; m/z (MH+): 334. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(NC)C1C=CC=CC=1.[CH3:10][NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=CC=CC=2)[C:14]=1CCC.Cl.[O:27]=[C:28]1[NH:37][C:36]2[N:35]=[CH:34][C:33](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:32][C:31]=2[CH2:30][CH2:29]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH2:12]([N:11]([CH3:10])[C:40](=[O:41])/[CH:39]=[CH:38]/[C:33]1[CH:34]=[N:35][C:36]2[NH:37][C:28](=[O:27])[CH2:29][CH2:30][C:31]=2[CH:32]=1)[C:13]1[CH:14]=[CH:15][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CNCc1ccccc1
Agent: Cl
Product: CN(Cc1ccccc1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 93 %

Procedure:
According to the procedure of Example 1 (a), except substituting benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.462 g, 93%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.37-8.33 (m, 1H), 8.08-8.06 (m, 1H), 7.54-7.49 (m, 1H), 7.37-7.21 (m, 6H), 4.82-4.61 (m, 2H), 3.10-2.85 (m, 5H), 2.56-2.49 (m, 2H); MS (APCI) m/e 322 (M+H)+.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:22])([C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([OH:17])=[O:16].C(=O)([O-])O.[Na+]>CO>[F:13][C:14]([F:22])([C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([O:17][CH3:2])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)C(F)(F)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(F)(F)C(C)(C)O
Yield: 65 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 73.3 g of Intermediate 3 in Example 3 and 300 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated. The residue was distilled in vacuum, obtaining 52.0 g (yield 65%) of methyl 2,2-difluoro-3-hydroxy-3-methylbutanoate.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[CH2:8]([C@H:15]([C:42]([NH:44][C@H:45]1[CH2:51][CH2:50][S:49][C@H:48]2[CH2:52][CH2:53][CH2:54][C@@H:55]([C:56]([O:58][CH3:59])=[O:57])[N:47]2[C:46]1=[O:60])=[O:43])[CH2:16][CH2:17][C@@H:18]([C:23](=[O:41])[NH:24][C@H:25]1[CH2:31][CH2:30][S:29][C@H:28]2[CH2:32][CH2:33][CH2:34][C@@H:35]([C:36]([O:38][CH3:39])=[O:37])[N:27]2[C:26]1=[O:40])[CH2:19][C:20]([OH:22])=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.CO>[CH2:8]([C@H:15]([C:42]([NH:44][C@H:45]1[CH2:51][CH2:50][S:49][C@H:48]2[CH2:52][CH2:53][CH2:54][C@@H:55]([C:56]([O:58][CH3:59])=[O:57])[N:47]2[C:46]1=[O:60])=[O:43])[CH2:16][CH2:17][C@H:18]([CH2:19][C:20]([O:22][CH3:2])=[O:21])[C:23]([NH:24][C@H:25]1[CH2:31][CH2:30][S:29][C@H:28]2[CH2:32][CH2:33][CH2:34][C@@H:35]([C:36]([O:38][CH3:39])=[O:37])[N:27]2[C:26]1=[O:40])=[O:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)CC(=O)O)C(=O)N21
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C[C@@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
TMS-diazomethane (2.0 M in ether, 0.0061 mL, 0.012 mmol) was added to a solution of (3R,6R)-6-benzyl-7-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-3-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamoyl)-7-oxoheptanoic acid (5.4 mg, 7.0 mmol) in DCM (0.06 mL) and MeOH (0.0062 mL). Gas evolution occurred. The reaction was stirred at rt for 1 hr. The reaction mixture was concentrated and triturated with hexanes. The solid was dried over vacuum to give methyl (4S,7S,10aS)-4-(((2R,5R)-5-benzyl-6-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)amino)-2-(2-methoxy-2-oxoethyl)-6-oxohexanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (5.0 mg, 0.0063 mmol, 91% yield) as a white solid. Anal. Calcd. for C38H52N4O10S2 m/z 788.7. found: 789.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (1H, d), 7.25-7.21 (2H, m), 7.19-7.11 (3H, m), 7.00 (1H, d), 5.39 (1H, t, J=4.7 Hz), 5.36 (1H, t, J=4.7 Hz), 5.21-5.16 (1H, m), 5.16-5.12 (1H, m), 5.10-4.98 (2H, m), 3.72 (3H, s), 3.69 (3H, s), 3.65 (3H, s), 3.28-3.10 (2H, m), 2.98-2.81 (3H, m), 2.77-2.62 (3H, m), 2.47-2.37 (3H, m), 2.34 (1H, dd, J=15.7, 3.6 Hz), 2.27-2.19 (1H, m), 2.08-1.95 (4H, m), 1.88 (1H, ddd, J=10.9, 7.0, 3.6 Hz), 1.76-1.47 (12H, m).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([N:16]=[C:17]=[S:18])=[CH:10][C:9]=2[F:19])[CH:7]=1>>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([NH:16][C:17]([NH2:1])=[S:18])=[CH:10][C:9]=2[F:19])[CH:7]=1
Reactant: N
Reactant: COc1cc(N=C=S)cc(F)c1-n1cnc(Cl)c1
Product: COc1cc(NC(N)=S)cc(F)c1-n1cnc(Cl)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
Step M (8): Methanolic ammonia (2.0 M, 5 mL, 10 mmol) was added to a flask charged with 4-chloro-1-(2-fluoro-4-isothiocyanato-6-methoxyphenyl)-1H-imidazole (230 mg, 0.811 mmol). After 2 h, the reaction mixture was concentrated in vacuo to afford 1-(4-(4-chloro-1H-imidazol-1-yl)-3-fluoro-5-methoxyphenyl)thiourea (244 mg, 100% yield). LC-MS (M+H)+ 301.1.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH3:18])[CH:16]=[CH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH3:18])/[CH:16]=[CH:17]/[CH2:20][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[Si](C)(C)C
Reactant: C=C[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: C[C@H](/C=C/C[Si](C)(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R)-2-methylbut-3-enoyl]-1,3-oxazolidin-2-one (0.65 mmol, 170 mg) and allyltrimethyl silane (1.9 mmol, 0.31 mL) in DCM (2 mL) at reflux was added 5 mol % of Grubbs' second generation catalyst (28 mg). After 72 hrs the solvent was removed in vacuo. The crude product was purified by column chromatography to a colourless oil. (83 mg, 77%) E/Z 3:1. NMR data of the mixture of E/Z isomers. 1H NMR (400 MHz, CDCl3): δ=7.21-7.36 (m, 5H), 5.64 (dt, J=8.1, 15.4, 1H), 5.41-5.58, (m, 2 HZ) 5.32-5.39 (m, 1H), 4.68-4.78 (m, 1 HZ) 4.59-4.68 (m, 1H), 4.38-4.48 (m, 1H), 4.14-4.19 (m, 2H), 3.30 (dd, J=3.28, 13.14, 1H), 2.78 (dd, J=9.6, 13.14, 1H), 1.48-1.63 (m, 2 HZ), 1.46 (d, J=8.1, 2H), 1.31 (d, J=6.8, 3 HZ), 1.30 (d, J=6.8, 3H), 0.0 (s, 9 HZ), −0.02 (s, 9H); 13C NMR (100 MHz, CDCl3): δ=175.5, 152.3, 135.4Z or E, 135.3Z or E, 129.7Z or E, 129.5Z or E, 128.9Z or E, 128.1Z, 127.3, 126.9, 126.1Z, 66.03, 66.0Z, 55.6, 55.5Z, 40.9, 37.9, 37.8Z, 35.8Z, 22.9, 19.0Z, 17.9, −1.8Z, −1.9; IR (CHCl3): v 2955, 1783, 1699, 1454, 1381, 853; HMRS required for C19H27NO3Si ([M+H]+) 346.1838 found 346.1847; [α]D23=−131.6 (c, 2, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].[C-]#N.[K+].O>CN(C)C=O>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:6]
Reactant: O=Cc1cccc(F)c1
Reactant: C=CC(=O)OC
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cccc(F)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 3-fluorobenzaldehyde (35.38 g, 285.07 mmol) in 35 mL dimethylformamide (DMF) was added to a heated (48° C.) solution of methyl acrylate (26.28 mL, 25.03 g, 290.7 mmol) and powdered KCN under Argon. The reaction mixture was stirred at 40° C. for 2 hours and then poured into 500 mL of water. This aqueous phase was extracted twice with 500 mL of Et2O and once with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, and then dried over MgSO4. The solvent was evaporated under reduced pressure to give 50.89 g (242.2 mmol, 84.93%) of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methyl ester as an oil. MS: 211 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:19])[CH3:18]>C(#N)C>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:19][CH2:17][CH3:18])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CCN
Solvent: CC#N
Product: CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 150 °C
Yield: 56.7 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.40 g, 1.30 mmol), ethanamine (70% in water, 3.0 ml, 37.8 mmol) and ACN (3.0 ml) was heated in a microwave oven at 150° C. for 20 min. The volatiles were evaporated in vacuum. The residue was chromathographed twice on a silica column using EtOAc/MeOH (2:1) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (0.2 g, 57%). The amine was converted into hydrochloric acid salt and crystallized from EtOH/DEE (0.33 g). The salt was washed with several portions of DEE. M.p. 203° C. 1H-NMR (400 MHz, MeOH): δ 7.50 (1H, dd, J1 8, J2 1.6), δ 7.41 (1H, d, J 1.6), δ 7.31 (1H, d, J 8), δ 5.27 (1H, t, J 4.8), δ 5.04 (2H, dd, J1 49, J2 16), δ 3.11 (3H, s), δ 3.01 (2H, t, J 4.0), δ 2.77 (2H, q, J 6.8), δ 1.17 (3H, t, J 7.2).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5](C)=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[N:25]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH:27]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2C)cc1C=O
Reactant: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3C)nc2OCOC)cs1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate (1.26 g) in tetrahydrofuran (40 mL) was added sodium hydride (60% in oil, 0.192 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazole-4-carbaldehyde (0.99 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:20-1:3, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (0.81 g, yield 57%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:13]1([CH2:12][CH2:11][CH2:10][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCc1ccccc1
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCC1CCCN(CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 10.07 g (87.43 mM) of 3-piperidinemethanol and 19.1 g (96.2 mM) of 1-bromo-3-phenylpropane in 150 ml of acetonitrile was added 18.1 g (131 mM) of potassium carbonate and the mixture was stirred at room temperature for one day. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to provide crude 1-(3-phenylpropan-1-yl)piperidine-3-methanol. This crude product was not purified but used as it was in the next reaction. To a solution of this crude 1-(3-phenylpropan-1-yl)piperidine-3-methanol and 14.6 ml (105 mM) of triethylamine in 150 ml of tetrahydrofuran was added a solution of 11.0 g (96.2 mM) of methanesulfonyl chloride in 50 ml of tetrahydrofuran dropwise under ice-cooling and the mixture was further stirred at the prevailing temperature for 0.5 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was dissolved in 500 ml of N,N-dimethylformamide, followed by addition of 17.8 g (96.2 mM) of potassium phthalimide, and the mixture was stirred at 100° C. overnight. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][N:6]2[N:5]=1.[CH2:16]=[O:17].Cl.O>S1(CCCC1)(=O)=O>[CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:13])[F:14])=[C:11]([CH2:16][OH:17])[N:6]2[N:5]=1
Reactant: COCc1nn2cc(C(F)(F)F)nc2s1
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COCc1nn2c(CO)c(C(F)(F)F)nc2s1
Temperature: 110 °C
Yield: 57.7 %

Procedure:
2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a2 (10 g, 42.16 mmol, 1 eq), formaldehyde (16 g, 421.6 mmol, 10 eq) and hydrochloric acid (37%, 8.2 ml, 2 eq) are diluted in sulfolane (250 ml). The reaction mixture is heated at 110° C. overnight. Water (500 ml) is added and the mixture is heated at 50° C. for 2 h. The solvent is then removed under reduced pressure. The residue is purified by chromatography over silicagel (gradient; eluent: CH2Cl2/MeOH/NH4OH from 100/0/0 to 99/1/0.1) to afford 6.5 g of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol a3 as a yellow solid.
Reaction SMILES: [CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)#[CH:30]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:30][CH2:29][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1
Reactant: C#Cc1cccnc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@](O)(CNC(=O)c1cnc(CCc2cccnc2)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1

Procedure:
To a solution of 0.1 g 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide in 2.0 ml of TEA is added at room temperature 0.015 g of bis(triphenylphosphine) palladium(II) chloride, 0.002 g cuprous iodide and 0.034 g meta-ethynylpyridine. The mixture is treated at 100° C., 1½ hours at the microwave. The starting material is consumed, as evidenced by HPLC. To the mixture is 1N HCl solution in water and ethyl acetate. The organic layer is washed with sodium bicarbonate and sodium chloride 10% solution in water. The residue is purified by chromatography in silica gel. The intermediate was hydrogenated under a hydrogen atmosphere in the presence of palladium on charcoal to yield after filtration and evaporation of the solvent the title compound as off-white oil, MS (ISP) 487.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.C([Mg]Cl)(C)C.CN([CH:20]=[O:21])C>C1COCC1.Cl.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH:20]=[O:21]
Reactant: COC(=O)c1cc(Br)c(Br)o1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C=O)o1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of 69.65 g (0.246 mol) of methyl 4,5-dibromo-2-furoate in 700 mL of dry THF was cooled to −45° C. under argon. To this solution 141.5 mL (0.282 mol) of isopropyl magnesium chloride 2M (Aldrich) was slowly added over 45 min at −43/−48° C. and the mixture was stirred for an additional hour. The resulting suspension was treated dropwise with 56.8 mL (0.737 mol) of anhydrous DMF (Aldrich, H2O<0.005%) over 30 min at −45° C. and stirred for 15 min at the same temperature. The reaction mixture was slowly warmed to +20° C., stirred for 1 hour and then it was slowly poured in a mixture of 1.2 L of HCl 1 M and 1.0 L of MTBE. The aqueous layer was separated and extracted twice with 1.0 L and 0.5 L of MTBE. The combined organic extracts were concentrated to dryness affording 57.81 g of crude material, which was crystallized from 120 mL of hot toluene and 230 mL of n-heptane. The resulting slurry was cooled to +4° C., aged for 2 h and filtered to afford 46.55 g of beige solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: Nc1ccnc2cc(C(F)(F)F)ccc12
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1onc(-c2ccccc2)c1C(=O)Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 70 °C
Yield: 55.8 %

Procedure:
5-Methyl-3-phenylisoxazole-4-carbonyl chloride (100 mg) and 4-amino-7-trifluoromethylquinoline (250 mg) were dissolved in dichlorormethane (5 mL) and pyridine (0.3 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/6) to give 5-methyl-3-phenyl-N-(7-trifluoromethyl-4-quinolinyl)-4-isoxazolecarboxamide (100 mg) as a white solid. 1H NMR (CDCl3): δ 2.91 (s, 3H), 7.33-7.69 (m, 9H), 8.39 (s, 1H, NH), 8.99 (d, J=5.1 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ-63.26; LCMS: ret. time: 34.04 min.; purity: 98.90%; MS (m/e): 398.77 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C@H:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[CH2:12]2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C@H:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(CCO[C@H]2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CCO[C@H]2CC[C@H](N)C2)cc1
Yield: 85.3 %

Procedure:
A mixture of benzyl {trans-3-[2-(4-methylphenyl)ethoxy]cyclopentyl}carbamate (291 mg, 0.82 g) and 5% palladium on carbon (150 mg) in ethanol (8 ml) was hydrogenated (hydrogen balloon) for three hours. The catalyst was removed by filtration through Celite. The filter cake was washed with ethanol (3×10 ml) and the filtrate was concentrated under reduced pressure to give an oil. The oil was filtered through a pad of silica gel eluting first with methanol: methylene chloride (10:90) to remove impurities, then with methanol: methylene chloride: conc. ammonium hydroxide (20:80:2), and the filtrate concentrated to give trans-3-[2-(4-methylphenyl)ethoxy]cyclopentanamine (154 mg, 86%), as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]=[N+:12]=[N-:13])[CH:5]=1.[C:15]([O:19][Si](C)(C)C)(=[O:18])[C:16]#[CH:17].CO>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:17]=[C:16]([C:15]([OH:19])=[O:18])[N:13]=[N:12]2)[CH:5]=1)=[O:14]
Reactant: C#CC(=O)O[Si](C)(C)C
Reactant: COC(=O)c1ccc(C)c(N=[N+]=[N-])c1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C)c(-n2cc(C(=O)O)nn2)c1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
3-Azido-4-methyl-benzoic acid methyl ester (878 mg, 4.60 mmol) and trimethylsilyl propiolate (777 mg, 5.05 mmol) were heated to 80° C. in a sealed tube overnight. The tube was cooled and the contents were mixed with 20 mL of MeOH. After 2 h, the mixture was poured into rapidly stirring cold water, and the resulting precipitate was filtered and dried under air to provide 823 mg of 1-(5-Methoxycarbonyl-2-methyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid.