Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH2:27])[CH2:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[CH:18][C:19]=1[Cl:20].CCN(C(C)C)C(C)C.[N:37]1[C:42]2[CH2:43][NH:44][CH2:45][CH2:46][C:41]=2[CH:40]=[N:39][C:38]=1[NH:47][C@@H:48]([CH3:51])[CH2:49][OH:50]>C(Cl)Cl.CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH:27][C:6]([N:44]2[CH2:45][CH2:46][C:41]3[CH:40]=[N:39][C:38]([NH:47][C@@H:48]([CH3:51])[CH2:49][OH:50])=[N:37][C:42]=3[CH2:43]2)=[O:7])[CH2:22][C:23]([F:24])([F:25])[F:26])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(CC(F)(F)F)c1ccc(Cl)c(Cl)c1
Reactant: C[C@@H](CO)Nc1ncc2c(n1)CNCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](CO)Nc1ncc2c(n1)CN(C(=O)NC(CC(F)(F)F)c1ccc(Cl)c(Cl)c1)CC2
Reaction time: 0.5 h

Procedure:
A 40 mL vial was charged with CDI (0.584 g, 3.60 mmol), 1-(3,4-dichlorophenyl)-3,3,3-trifluoropropan-1-amine (0.929 g, 3.60 mmol), DIPEA (1.88 mL, 10.8 mmol), DCM (7 mL) and DMF (2 mL). The mixture was stirred for 30 min then a solution of 138 (0.750 g, 3.60 mmol) and DIPEA (1.88 mL, 10.8 mmol) in DCM (3 mL) was added and the mixture stirred for 18 h. The reaction mixture was washed with brine (4 mL) and the organic phase isolated and concentrated. The residue was resuspended in EtOAc and washed with brine (2×50 mL) and concentrated in vacuo. The crude product was purified by reverse phase chromatography (Horizen C18 Biotage 40M) eluting with a MeCN/H2O gradient (eluted at ca. 50% MeCN) to afford 925 mg which was separated by chiral HPLC chromatography and repurified as described in example 19 to afford 0.212 g (23%) of I-34 as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.55 (m, 1H), 7.49 (d, 1H), 7.31 (m, 1H), 5.20 (m, 1H), 4.41 (q, 2H), 4.06 (m, 1H), 3.65 (t, 2H), 3.56 (m, 2H), 2.79 (m, 4H), 1.20 (d, 3H); m/z (APCI-pos) M+1=492.0.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>N1C=CC=CC=1.C(Cl)Cl>[C:32]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)=[CH:22][C:23]=1[Cl:28])(=[O:33])[CH2:31][CH2:30][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)OC(=O)CCC)o2)cc1Cl
Reaction time: 23 h

Procedure:
To a solution of 2-chloro-4-((1R,2S)-1-(5-(3-chloro-4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (example 37) (96.5 mg, 0.23 mmol) in pyridine (0.6 mL) and CH2Cl2 (4 mL) was added n-butyryl chloride (0.12 mL, 1.15 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange/brown viscous oil, which was purified by flash chromatography over silica gel (20-25% EtOAc in hexanes) to provide the title compound as an off white solid (116 mg, 90%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.11 (d, J=2.0 Hz, 1H), 8.03 (dd, J=2.2, 8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.67 (dq, J=5.7, 6.5 Hz, 1H), 5.45 (dd, J=5.7, 8.6 Hz, 1H), 2.67 (t, J=7.4 Hz, 2H), 2.33-2.28 (m, 2H), 1.83-1.72 (m, 2H), 1.66-1.52 (m, 2H), 1.47 (d, J=6.5 Hz, 3H), 1.04 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:12][C:9]3([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:10][CH2:11]3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: NC1(c2cc(F)ccc2F)CC1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NC1(c2cc(F)ccc2F)CC1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 1-(2,5-difluorophenyl)cyclopropanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Br)cc1
Reaction time: 1 h

Procedure:
Methane sulfonyl chloride (2.4 ml, 0.031M) was added to a solution of 4-bromo-aniline (5.28 g, 0.031M) and pyridine (2.5 ml, 0.031M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a white solid (6.37 g). 1H NMR (CDCl3): 2.97 (s, 3H), 6.81 (d, J=2.56 Hz, 2H), 7.25 (d, J=2.56 Hz, 2H),).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([O:21][P:22]([CH2:27][N:28]1[C:32]([SH:33])=[N:31][N:30]=[N:29]1)([O:24][CH2:25][CH3:26])=[O:23])[CH3:20].[P:34]([CH2:38][N:39]1[C:43]([SH:44])=[N:42][N:41]=[N:40]1)([OH:37])([OH:36])=[O:35].C(=O)(O)[O-].[Na+]>>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH:5]([S:44][C:43]3[NH:42][N:41]=[N:40][N:39]=3)[CH2:27][P:22]([O:21][CH2:19][CH3:20])([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][S:14][C@H:9]12.[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH:5]([S:33][C:32]3[NH:28][N:29]=[N:30][N:31]=3)[CH2:38][P:34]([OH:37])([OH:36])=[O:35])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCOP(=O)(Cn1nnnc1S)OCC
Reactant: O=P(O)(O)Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1)OCC
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(C(CP(=O)(O)O)Sc3nnn[nH]3)CS[C@H]12

Procedure:
Reaction of 7-aminocephalosporanic acid with 1-diethoxyphosphinylmethyltetrazole-5-thiol and 1-phosphonomethyltetrazole-5-thiol in the presence of 1 and 3 molecular equivalents of sodium bicarbonate, respectively, as described in Example 10 gives 7β-amino-3-(1-diethoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 7β-amino-3-(1-phosphonomethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, respectively.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[F:5][C:6]1([F:50])[CH2:11][CH2:10][CH:9]([C:12]2[C:21]3[CH:20]([OH:22])[CH2:19][C:18]([CH3:24])([CH3:23])[CH2:17][C:16]=3[N:15]=[C:14]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]4[N:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=4)[CH2:27][CH2:26]3)[C:13]=2[CH:38]([F:49])[C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH2:8][CH2:7]1>>[F:50][C:6]1([F:5])[CH2:7][CH2:8][CH:9]([C:12]2[C:21]3[CH:20]([OH:22])[CH2:19][C:18]([CH3:23])([CH3:24])[CH2:17][C:16]=3[N:15]=[C:14]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]4[N:36]=[CH:35][C:34]([O:37][CH:1]([CH3:3])[CH3:2])=[CH:33][N:32]=4)[CH2:29][CH2:30]3)[C:13]=2[CH:38]([F:49])[C:39]2[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=2)[CH2:10][CH2:11]1
Reactant: CC(C)I
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Product: CC(C)Oc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 13 were performed except for using isopropyl iodide instead of ethyl iodide and setting the reaction temperature to 50° C., and from 60 mg (90 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 54 mg of the title compound was obtained as a white solid (yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([F:9])[F:8])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[F:8][CH:7]([F:9])[N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nnn(C(F)F)n1
Product: O=C(Nc1nnn(C(F)F)n1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 143-145° and MS: (neg. ions): m/e=328.1 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-difluoromethyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH:34]([CH3:36])[CH3:35])[CH:33]=4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37].CO>O1CCOCC1>[ClH:37].[CH:34]([N:32]1[CH:33]=[C:29]([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH:30]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reaction time: 2 h
Yield: 117.3 %

Procedure:
To a suspension of tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.090 g, 0.185 mmol) in 1.5 mL of dioxane was added hydrogen chloride (1.8 mL, 7.20 mmol) in dioxane at ambient temperature with stirring. After 2 hours, 0.5 mL of methanol was added to dissolve all solids and the reaction was concentrated under reduced pressure. The crude was suspended in DCM, sonicated, and concentrated three times and the resulting crude was dried on high vacuum for 3 hours to afford 2-(3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.116 g, 0.217 mmol, 93% yield). MS (apci) m/z=388.2 (M+H).
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4]>O1CCOCC1.C(O)C>[N+:3]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=[N+]([O-])CCc1ccc2ccccc2c1
Yield: 6.7 %

Procedure:
To a suspension of sodium borohydride (4 g) in a mixture of dioxane (85 ml) and ethanol (30 ml) was added dropwise a solution of 2-(2-nitroethenyl)naphthalene (100 g) in dioxane (90 ml) over 30 minutes. The flask was cooled with a cold water bath during addition. Stirring was maintained for an additional 11/2hours. Ice (100 ml) and 50% aqueous acetic acid room temperature, concentrated in vacuo and extracted with methylene chloride. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo to yield an oil which was crystallized from acetic acid to give the title compound (6.79 g) as a yellow solid, m.p. 59°-60° C.
Reaction SMILES: O[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16].C(Cl)(=O)C([Cl:20])=O.O>CN(C=O)C>[Cl:20][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)c(Cl)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 19 mmol) in DMF (30 mL) at 0° C. was treated with oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then stirred at 80° C. for 3 h under a CaCl2 drying tube. The mixture was allowed to cool to RT, poured in to iced water (100 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water and MeOH to afford methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ: 8.04 (1H, d), 7.77 (1H, d), 4.04 (3H, s), 3.97 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 55.6 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (150 mg, 0.3 mmol), 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 143, step C) (87 mg, 0.27 mmol), and p-toluenesulfonic acid (135 mg, 0.71 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (121 mg, 0.15 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.73 (dd, J=8.70, 2.11 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.39-7.47 (m, 2H), 7.32-7.39 (m, 1H), 7.24 (d, J=8.79 Hz, 1H), 7.18 (t, J=8.06 Hz, 2H), 6.92 (t, J=7.05 Hz, 1H), 6.66 (d, J=2.38 Hz, 1H), 6.53 (d, J=5.31 Hz, 1H), 6.44-6.49 (m, 1H), 4.24 (q, J=6.90 Hz, 2H), 4.05 (q, J=6.96 Hz, 2H), 3.30-3.34 (m, 2H), 3.08-3.14 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.87 Hz, 2H), 2.54-2.59 (m, 4H), 1.41 (t, J=6.87 Hz, 3H), 1.23 (t, J=6.96 Hz, 3H). MS (ESI): 797 [M+H]+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1>C(O)C>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4]
Reactant: OCCNCCO
Reactant: Brc1nccs1
Solvent: CCO
Product: OCCN(CCO)c1nccs1
Yield: 24.7 %

Procedure:
In a sealable tube were successively added diethanolamine (3.46 mL, 35.8 mmol) and 2-bromothiazole (1.538 mL, 17.07 mmol), under nitrogen. The tube was sealed and the mixture was irradiated in the microwave at 130° C. for 30 min. The residue was dissolved in 5:95 ethanol:dichloromethane and chromatographed on silica (CombiFlash, 5-20%, ethanol in dichloromethane) to afford 2,2′-(1,3-thiazol-2-ylimino)diethanol (795 mg, 4.22 mmol, 24.74% yield) as a pale oil.
Reaction SMILES: [Na].[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[CH:4][C:5]#[N:6].[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:17]([O:16][C:15](=[O:19])[NH:2]/[C:3](/[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[CH:4]\[C:5]#[N:6])[CH3:18]
Reactant: CCOC(=O)OCC
Reactant: N#CC=C(N)c1ccc(F)cc1F
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1F

Procedure:
At 40° C., 769 mg (33.44 mmol) of sodium were dissolved in ethanol (41 ml). 4.14 g (22.29 mmol) of 3-amino-3-(2,4-difluorophenyl)prop-2-enonitrile and 5.79 g (49 mmol) of diethyl carbonate were added, and the reaction solution was stirred under reflux for 4 h. 200 ml of ethyl acetate and 150 ml of water were added to the reaction mixture and the pH was adjusted with hydrochloric acid to pH=5. The organic phase was separated off, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was triturated with diisopropyl ether and the white precipitate was filtered off with suction. More product was obtained by separating the mother liquor by preparative HPLC (Method 11). Drying under high vacuum gave a total of 4.92 g (49% of theory) of the product as a mixture of E and Z isomers which was used without further purification.
Reaction SMILES: [F:1][C@@H:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.S(C1C=CC(C)=CC=1)(O[CH2:38][C@@H:39]([O:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][O:47]1)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=O)=O>O>[F:1][C@@H:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:38][C@@H:39]([O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:14][CH:13]=2)=[N:8][CH:7]=1
Reactant: CCCC[C@H](F)CCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCC[C@@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC[C@@H](COc1ccc(-c2ncc(OCC[C@@H](F)CCCC)cn2)cc1)OC1CCCCO1
Yield: 110.7 %

Procedure:
In a reaction flask were charged 3.5 g of 5-[3-(S)-fluoroheptyloxy]-2-(4-hydroxyphenyl)pyrimidine synthesized in the same manner as in steps 1 to 7 of Example 1, 3.17 g of potassium carbonate, 70 ml of DMF, and 6.4 g of 2-(S)-tetrahydropyranyloxyheptyl tosylate in a nitrogen stream, and the mixture was allowed to react at 80° C. for one day. After cooling, water was added thereto, the reaction mixture was extracted with toluene, and the solvent was removed from the extract to obtain 7.6 g of a crude product. Purification by silica gel column chromatography gave 6.4 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Br:18])#[N:13]>CN(C)C=O.C(OCC)(=O)C>[BrH:18].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([C:12]#[N:13])[CH:15]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: N#Cc1cccc(CBr)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: N#Cc1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 105 °C
Reaction time: 5 h
Yield: 28.3 %

Procedure:
(Step 2) To a solution of 2-amino-5-chloronicotinamide (0.14 g) obtained in Step 1 in N,N-dimethylformamide (3 ml) was added 3-cyanobenzylbromide (0.19 g), and the mixture was stirred at 105° C. for 5 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (85 mg).
Reaction SMILES: C1(S([CH:10]([CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=O)=O)C=CC=CC=1>CO.C(OCC)(=O)C.CCCCCC.[Na].[Hg]>[C:21]([OH:23])(=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCC(=O)O)S(=O)(=O)c1ccccc1
Agent: [Hg]
Agent: [Na]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 50.4 %

Procedure:
To a solution of (17Z,20Z,23Z,26Z)-12-(phenylsulfonyl)dotriaconta-17,20,23,26-tetraenoic acid (0.0643 g, 0.105 mmol) in methanol (8 mL) was added Na2HPO4 (0.074 g, 0.525 mmol) and 10% sodium amalgam (5.16 g, 2.308 mmol) and the resulting reaction mixture was stirred under nitrogen at room temperature for 40 h. The solvent was decanted and acidified (pH 4) with 1M HCl. The aqueous phase was extracted with DCM (3×10 mL), washed with brine (2×10 mL), dried over MgSO4, filtered and evaporated. The product from the crude was isolated by flash chromatography using 25% ethyl acetate/hexane as eluent to afford the title product as a light yellow oil (0.025 g, 51%). 1H NMR (CDCl3): δ 5.36 (m, 8H), 2.79 (m, 6H), 2.28 (t, 2H, J=6.7 Hz), 1.99 (m, 4H), 1.61 (m, 2H), 1.51-1.18 (m, 30H), 0.97 (t, 3H, J=6.8 Hz). m/z (APCI) 473.62 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:27]([C:21]1[CH:22]=[CH:23][C:24]([C:10](=[O:12])[CH2:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:25][CH:26]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCc1ccccc1
Reactant: N#Cc1cccc(CC(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Temperature: 0 °C
Yield: 29.7 %

Procedure:
A mixture of 3-cyanophenylacetic acid (13 g, 0.08 mole) and thionyl chloride (100 ml) is heated under reflux for 90 minutes. The excess thionyl chloride is removed by evaporation under reduced pressure. The residue is dissolved in methylene chloride (20 ml) and the resulting solution added to aluminum chloride (16.2 g, 0.12 mole) in methylene chloride (200 ml) with vigorous stirring. A solution of 1-phenylheptane (14.3 g, 0.12 mole) in methylene chloride (50 ml) is then added over 20 minutes. The reaction mixture is heated under reflux (1 hour) and then poured into ice water (1 liter) with vigorous stirring. The mixture is extracted twice with ether (600 ml and 100 ml). The extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel (hexane/ether) to give 3-(4-n-heptylphenacyl)benzonitrile (7.6 g) as a White crystalline solid, m.p. 68° C. Then, 3-(4-n-heptylphenacyl)benzonitrile (1.5 g, 4.7 mole) is heated under reflux (1 hour) in a mixture of 75% aqueous sulfuric acid (12 g) and acetic acid (12 g). The reaction mixture is diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting yellow solid is chromatographed on silica gel (hexane:ether:acetic acid; 60:40:1) and recrystallized from heptane to give 3-(4-n-heptylphenacyl)benzoic acid (1 g) as a pale yellow crystalline solid, 128°-133°C.