Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:4]2[N:3]=1.CC1(C)C(C)(C)OB(C2C=C(C)C=CC=2OC(C(C)C=C)C)O1.BrC1C=C(N)NN=1.[CH2:48]([O:51][C:52]1([CH3:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH:49]=[CH2:50].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:48]([O:51][C:52]1([CH3:58])[CH2:53][CH2:54][N:55]([C:9]2[N:4]3[N:3]=[C:2]([Br:1])[CH:17]=[C:5]3[N:6]=[C:7]([CH3:16])[C:8]=2[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:56][CH2:57]1)[CH:49]=[CH2:50]
Reactant: C=CCOC1(C)CCNCC1
Reactant: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Agent: C=CC(C)C(C)Oc1ccc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: Nc1cc(Br)n[nH]1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c(CC(=O)OC)c(C)nc3cc(Br)nn23)CC1
Yield: 97 %

Procedure:
A solution of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (prepared according to the procedure for intermediate 4 starting from 3-bromo-1H-pyrazol-5-amine; 13.4 g, 41.9 mmol, 1 equiv), 4-(allyloxy)-4-methylpiperidine (7.16 g, 46.1 mmol, 1.1 equiv), and DIEA (17.6 mL, 101 mmol, 2.4 equiv) in DMF (84 mL) was heated at 60° C. for 2 h. The reaction was then added to water and extracted with ether (×2). Combined ether extracts dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-50% EtOAc/hex) to provide methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (17.7 g, 97%). 1H NMR (500 MHz, CDCl3) δ 6.52 (s, 1H), 6.02 (ddt, J=17.2, 10.4, 5.2 Hz, 1H), 5.43 (dd, J=17.2, 1.6 Hz, 1H), 5.22 (dq, J=10.4, 1.5 Hz, 1H), 3.99 (dt, J=5.2, 1.6 Hz, 2H), 3.77 (s, 3H), 3.79-3.76 (m, 2H), 3.70-3.56 (m, J=7.4 Hz, 2H), 3.33 (br. s., 2H), 2.50 (s, 3H), 1.97-1.89 (m, 2H), 1.87-1.78 (m, J=9.3 Hz, 2H), 1.32 (s, 3H). LCMS (M+1)=437.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[N:16][O:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:23](=[O:24])[O:12][N:11]=[C:10]2[C:13]2[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[N:16][O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Product: COCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A mixture of N-(3-bromo-4-fluorophenyl)-N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (76.5 g, 0.204 mol), 1,1′-carbonyldiimidazole (49.7 g, 0.307 mol), and ethyl acetate (720 mL) was heated to 60° C. and stirred for 20 min. LCMS indicated reaction completed. The reaction was cooled to room temperature, washed with 1 N HCl(2×750 mL), dried over sodium sulfate, and concentrated to give the desired product (80.4 g, 98%) as a crude brown solid. LCMS for C13H12BrFN5O4 (M+H)+: m/z=400.0, 402.0. 1H NMR (400 MHz, DMSO-d6): δ 7.94 (t, J=8.2 Hz, 1H), 7.72 (dd, J=9.1, 2.3 Hz, 1H), 7.42 (m, 1H), 6.42 (t, J=5.7 Hz, 1H), 3.46 (t, J=5.4 Hz, 2H), 3.36 (t, J=5.8 Hz, 2H), 3.26 (s, 3H).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[H][H].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH2:21][CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.9 %

Procedure:
A solution of Boc-Ser-OH (1, 2.05 g, 10 mmol) in DMF (30 ml) is added to a stirred suspension of sodium hydride (60 wt % in mineral oil, 880 mg, 22 mmol) in DMF (30 ml) at 0° C. After the evolution of hydrogen gas ceased, allyl bromide (0.95 ml, 11 mmol) is added to the milk-colored solution. The resulting mixture is stirred at room temperature for 5 h to give a clear solution. The solvent is removed in vacuo, water (50 ml) is added, and the aqueous solution is extracted with ether (2×20 ml.) The aqueous solution is then acidified to pH 3.0 with 1.0 N HCl and extracted further with ethyl acetate (5×20 ml.) The combined ethyl acetate extracts are washed with water (20 ml), brine (20 ml), dried over anhydrous magnesium sulfate, and concentrated to give crude Boc-Ser(allyl)-OH (1.96 g) as a light yellow oil. A solution of this oil in ether (30 ml) is treated with dicyclohexylamine (1.594 ml, 8.0 mmol), the solvent removed, and the residue triturated with 1:9 ethyl acetate/hexane to yield 2 (2.26 g) as a colorless solid. An additional amount of 2 (0.58 g) is isolated from the trituration solution also as a colorless solid.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:13][C:14]1[CH:15]([OH:22])[CH2:16][C:17](=[CH2:21])[C:18]=1[CH2:19][CH3:20].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7]([O:22][CH:15]2[CH2:16][C:17](=[CH2:21])[C:18]([CH2:19][CH3:20])=[C:14]2[CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: C=C1CC(O)C(C)=C1CC
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=C1CC(OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)C(C)=C1CC
Reaction time: 8 h
Yield: 86.3 %

Procedure:
625 mg of (1R)-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride was added under ice-water cooling to a mixed solution of 400 mg of (RS)-2-methyl-4-methylidene-3-ethylcyclopent-2-en-1-ol, 5 mg of 2,6-di-t-butyl-4-methylphenol and 274 mg of pyridine in 6 ml of toluene. The reaction was continued at an ambient temperature for eight hours. The reaction solution was added to a 5% citric acid solution under ice-water cooling, and extracted three times with diethyl ether. The combined ether layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to yield 781 mg of (RS)-2-methyl-4-methylidene-3-ethyl-2-cyclopenten-1-yl (1R)-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (Compound No.5). Yield 82%. (Eluent: n-hexane/ethyl acetate=30/1, 2,6-di-t-butyl-4-methylphenol 0.1%) nD23 1.5251
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([C:55]([OH:57])=O)=[C:27]([CH2:42][N:43]3[CH2:48][CH2:47][CH:46]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH2:45][CH2:44]3)[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[N:29]2)=[CH:24][C:23]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])[CH3:20].[F:64][C:65]([F:75])([F:74])[C@H:66]([NH2:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([C:55]([NH:73][C@H:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:65]([F:64])([F:74])[F:75])=[O:57])=[C:27]([CH2:42][N:43]3[CH2:44][CH2:45][CH:46]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH2:47][CH2:48]3)[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[N:29]2)=[CH:24][C:23]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:59])=[O:60])[CH3:20]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(=O)(=O)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2cc1S(=O)(=O)C(C)C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
T3P in ethyl acetate (1.273 mL of a 50% solution, 2.001 mmol) was added to a stirred solution of 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1 g, 1.539 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.391 g, 1.847 mmol), and N,N-diisopropylethylamine (0.538 mL, 3.08 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 16 h, diluted with saturated aqueous sodium bicarbonate, and extracted with methylene chloride (three times). The combined organic extracts were washed with saturated sodium bicarbonate, brine, dried, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-5% methanol/methylene chloride) to afford 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.450 g, 34% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ10.00 (br. s., 1H), 8.48 (br. s., 1H), 7.97 (s, 1H), 7.86 (d, J=7.55 Hz, 2H), 7.71-7.78 (m, 2H), 7.60-7.68 (m, 2H), 7.42-7.47 (m, 3H), 6.20 (quin, J=8.81 Hz, 1H), 4.39 (q, J=6.80 Hz, 2H), 3.72-3.86 (m, 1H), 3.50 (br. s., 4H), 3.44 (br. s., 1H), 3.18 (br. s., 1H), 2.39 (br. s., 1H), 2.33 (br. s., 1H), 2.26 (br. s., 4H), 2.11 (br. s., 1H), 1.68 (br. s., 2H), 1.53 (br. s., 1H), 1.44 (t, J=6.80 Hz, 3H), 1.12-1.37 (m, 7H), 0.74-0.99 (m, 2H); MS (m/z) 807.2 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[C:11]([C:14]#[N:15])[C:12]#[N:13])SC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:17][NH2:18]>CCO>[NH2:13][C:12]1[NH:18][N:17]=[C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]=1[C:14]#[N:15]
Reactant: NN
Reactant: CSC(NC1CCCCC1)=C(C#N)C#N
Solvent: O
Solvent: CCO
Product: N#Cc1c(NC2CCCCC2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((cyclohexylamino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(cyclohexylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:22]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: C1CNCCN1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CCNCC2)c(=O)n(C)c1=O

Procedure:
Example 43 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and piperazine. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.0 Hz, 1H) 7.56 (d, J=8.0 Hz, 1H) 6.99 (t, J=8.0 Hz, 1H) 3.93 (m, 1 H) 3.77 (m, 1H) 3.51 (s, 3H) 3.25 (s, 3H) 3.17 (m, 4H) 2.98 (m, 1H) 2.52 (m, 1H). [M+H] calc'd for C17H19FIN5O3, 488; found, 488.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Br)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.74-6.66 (m, 13H), 5.13-5.02 (m, 1H), 3.73-3.51 (m, br, 2H), 3.05-2.83 (br, 2H), 2.83-2.62 (br, 4H), 2.62-2.42 (m, br, 2H), 2.10-1.80 (m, br, 6H), 1.65-1.37 (m, br, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 562.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:8][N:7]1[C:2]([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:12]=[O:13])[C:4](=[O:11])[N:5]([CH3:10])[C:6]1=[O:9]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: Sc1ccccc1
Product: Cn1c(Sc2ccccc2)c(C=O)c(=O)n(C)c1=O

Procedure:
The process described in Method D was followed. 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (1.50 g, 7.40 mmol) and benzenethiol were used to obtain the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)(=[O:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:34][O:35][C:36]1[C:41]2[N:42]=[C:43]([NH2:45])[S:44][C:40]=2[C:39]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]([NH:45][C:43]2[S:44][C:40]3[C:39]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:38][CH:37]=[C:36]([O:35][CH3:34])[C:41]=3[N:42]=2)=[O:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(=O)O[C@@H]1CC[C@H](CC(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](OC(C)=O)C3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (rac)-(cis)-3-(acetyloxy)-cyclopentaneacetic acid (770 mg, 4.1 mmol) and N,N-dimethylformamide (0.01 ml, 0.13 mmol) in dichloromethane (10 ml) were added oxalyl chloride (1.4 ml, 17 mmol) and the resulting solution stirred for 18 h at ambient temperature. After evaporation of the volatile components in vacuo, the residue was taken up in toluene (10 ml) and again evaporated to dryness. The obtained acid chloride was then dissolved in dichloromethane (20 ml) and subsequently treated with N-ethyl-diisopropyl amine (2.5 ml, 15 mmol) and 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (960 mg, 3.6 mmol). After stirring for 2 h at ambient temperature and another hour at 50° C., the mixture was cooled to room temperature and treated with saturated aqueous sodium hydrogen carbonate (15 ml) and extracted twice with dichloromethane (20 ml each). After drying over magnesium sulphate and evaporation of the solvents, flash chromatography (silica, eluent dichloromethane/ethyl acetate 85:15) afforded (rac)-(cis)-2-(3-acetoxy-cyclopentyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide as off-white solid. Separation by preparative chiral HPLC (Chiralpack AD, eluent heptane/isopropanol 85:15) afforded the title compound as first eluting isomer. Light yellow solid (4% yield). MS: m/e=434(M+H+), mp 171-172° C.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Cl:13][C:14]([Cl:52])([Cl:51])[CH2:15][O:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:50])[C@@H:26]([NH:42][C:43](OC(C)(C)C)=[O:44])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:29]=2)[NH:20]1)=[O:18].C(N(CC)C(C)C)(C)C.[C:62]([O:66][C:67]([NH:69][C@@H:70]([CH2:74][C:75]1[CH:80]=[CH:79][C:78]([O:81][CH3:82])=[CH:77][CH:76]=1)C(O)=O)=[O:68])([CH3:65])([CH3:64])[CH3:63]>ClCCl.C(#N)C>[Cl:13][C:14]([Cl:52])([Cl:51])[CH2:15][O:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:50])[C@@H:26]([NH:42][C:43](=[O:44])[C@@H:70]([NH:69][C:67]([O:66][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:68])[CH2:74][C:75]2[CH:76]=[CH:77][C:78]([O:81][CH3:82])=[CH:79][CH:80]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:37])[CH3:36])[CH:29]=2)[NH:20]1)=[O:18]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N2CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N2)cc1
Temperature: 25 °C
Reaction time: 1.42 h
Yield: 66.5 %

Procedure:
Trimethylsilyltrifluoromethanesulfonate (341 μL, 1.89 mmol) was added dropwise to a solution of the (S)-1-{(S)-2-tert-butoxycarbonylamino-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (670 mg, 1.05 mmol) in dichloromethane (15 mL) at 0° C. under N2 and the reaction was stirred for 85 minutes. To this was added N,N-diisopropylethylamine (730 μL, 4.19 mmol) and the reaction was warmed to room temperature. The volatiles were evaporated to afford a colourless foam which was dissolved in acetonitrile (15 mL). To this solution was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (477 mg, 1.26 mmol), (S)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid (340 mg, 1.15 mmol) and N,N-diisopropylethylamine (730 μL, 4.19 mmol) and the reaction was stirred for 18 h. The volatiles were evaporated and the residue partitioned between pH=7 buffer and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the volatiles evaporated. The residue was purified by silica chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:1 to afford the title compound (570 mg, 67%) as a colourless foam. 1H NMR (300 MHz, CDCl3) δ0.18 (s, 6H), 1.00 (s, 9H), 1.43 (s, 9H), 1.45-1.60 (m, 2H) 1.73-1.83 (m, 1H), 1.85-1.95 (m, 1H), 2.30 (br s, 1H), 2.65-3.00 (m, 5H), 3.50 (d, J=11.2 Hz, 1H), 3.80 (s, 3H), 4.24-4.37 (m, 2H), 4.65 (d, J=11.8 Hz, 1H), 4.95 (d, J=11.8 Hz, 1H), 4.96-5.04 (m, 1H), 5.62-5.75 (m, 1H), 6.45 (d, J=8.3 Hz, 1H), 6.64-6.75 (m, 2H), 6.78-6.86 (m, 3H), 7.07-7.16 (m, 3H). LCMS (m/z) 817.3 [M+H], Tr=5.89 min.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[CH:25]1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=C[CH:26]=1.C1(C)C(C)=CC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C>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.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:23]=[C:22]([CH:25]=[CH2:26])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a mixture of 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (30 mg, 0.083 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.017 mmol) and xylene (1.5 mL) was added vinyl(tri-butyl)tin (0.073 mL, 0.25 mmol), and the solution was stirred at 130° C. for 3 hours. After cooling, water and ethyl acetate were added to the reaction solution for extraction, which was then washed with brine. The solvent was evaporated in vacuo, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (19 mg, 0.054 mmol, 65%) was obtained as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:23][CH:24]([CH3:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([CH:24]([CH3:34])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCNC(C)Cc1ccc(OC)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1)C(C)Cc1ccc(OC)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and ethyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO6 [M+H]+: 430.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.P(Br)(Br)([Br:19])=O>C1(C)C=CC=CC=1.C(#N)C>[Br:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-hydroxyquinoline-2-carboxylate (10.0 g, 46.0 mmol) and phosphorus oxybromide (13.2 g, 46.0 mmol) in 100 mL of toluene and 10.0 mL acetonitrile was heated at 75° C. for 1.5 h. The reaction mixture was cooled to room temperature, quenched slowly with water, and extracted with ethyl acetate. The organic fraction was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to afford ethyl 4-bromoquinoline-2-carboxylate that gave a mass ion (ES+) of 280.1 (79Br) for M+H+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(N(CC)CC)C.CO>C(Cl)Cl>[CH2:1]([NH:8][C:14]1[CH:15]=[C:10]([Cl:9])[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Clc1cc(NCc2ccccc2)ncn1
Yield: 78.7 %

Procedure:
Benzyl amine (0.697 ml, 6.76 mmol) was added to 4,6-dichloropyrimidine (1.0 g, 6.76 mmol) neat causing a vigorous reaction and color change. The reaction was slowly diluted with methylene chloride resulting in a white precipitate. 1 ml of triethyl amine was added and TLC indicated conversion to product (5% MeOH:methylene chloride). The reaction was loaded directly onto a silica and purified (eluent:2% MeOH:methylene chloride) giving 1.17 g (5.32 mmol) of 12 as a yellow wax in 79% yield.