Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([Cl:29])=[O:28]>C1C=CC=CC=1>[ClH:29].[CH3:17][O:16][C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:9]2[CH:10]3[N:5]([CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH2:4][CH2:3][CH:2]([NH:1][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH3:22])[CH:25]=1)[CH2:11]3
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1cccc(C(=O)NC2CCN3CCc4cc(OC)c(OC)cc4C3C2)c1
Product: Cl
Yield: 18.2 %

Procedure:
A mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9, 10-dimethoxy-2H-benzo[a]quinolizine (5 g, 0.019 mole), 150 ml of benzene and 30 ml of 20% NaOH was cooled to below 10° whereupon 3-methoxy benzoyl chloride (3.3 g, 0.02 mole) was added dropwise with stirring. The mixture was stirred in the cold for 1 hour and filtered to remove the solid whereupon the solid was chromatographed over silica gel using benzene-methanol (6:1) as eluant. The major fraction (4.1 g) was converted to the HCl salt with hydrogen chloride in 2-propanol and the solvent was removed in vacuo. The salt was crystallized from methanol-ether to yield 1.5 g of the desired product, m.p. (decomposed at 217°-9°). This compound conforms to Formula II where R1 and R2 are --OCH3R3 is H and R4 is ##STR16##
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:10][C:11]1[N:12]=[CH:13][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccccc2C#N)cn1

Procedure:
As described for example 84a, 2-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup the title compound was obtained as a white solid (yield: 60%). MS: m/e=184.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[CH3:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:15]([OH:20])[OH:16]
Reactant: CSc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccccc1B(O)O
Reaction time: 0.42 h
Yield: 84.9 %

Procedure:
2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to −75° C. n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 minutes. After stirring 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temp for 16 hours. The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 hours and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2O. These Et2O washes were dried over Na2SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1H NMR (CDCl3): δ 8.01 (dd, 1H, J=7.3, J′=1.4), 7.53 (dd, 1H, J=7.7, J′=1.1), 7.43 (td, 1H, J=7.3, J′=1.8), 7.34 (td, 1H, J=7.3, J′=1.5), 6.22 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1.C(N(CC)C(C)C)(C)C.[C:22]([OH:26])([CH3:25])([CH3:24])[CH3:23].[OH-].[Na+]>O.C(OCC)(=O)C>[C:22]([O:26][C:1](=[O:2])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)O
Reactant: Nc1cccc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Temperature: -15 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
64 mL of ethyl acetate were added to a reaction system and cooled to about −15° C. with a salt and ice bath followed by blowing in 10.6 g (107 millimoles) of phosgene. A mixed solution containing 5.5 g (42.8 millimoles) of 2-amino-6-chloropyridine, 11.1 g (85.6 millimoles) of N,N-diisopropylethylamine, 6.34 g (85.5 millimoles) of t-butanol and 43 mL of ethyl acetate were dropped into this phosgene solution over the course of 2.5 hours while holding the internal temperature at −15° C. to −5° C. Following completion of dropping, the solution was stirred for 3 hours at the same temperature range. Next, 50 mL of water and 23.2 g of 28% sodium hydroxide were sequentially added while holding the internal temperature at 0° C. or lower. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and concentrated under reduced pressure. The resulting crude crystals were subjected to quantitative analysis by HPLC. The target (6-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at a yield of 93%. There was hardly any urea compound formed.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5](O)=[CH:4][CH:3]=1)O.[C:9](O)(=[O:12])C=C.[C:14](O)(=O)C=C.C(O)(=O)C=C.C(C(CO)(CO)CC)O.[C:33]([O:44][CH2:45]COC(=O)C=C)(=[O:43])[C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)C([O-])=O>C(OC)(=O)C1C(=CC=CC=1)C(OC)=O>[CH3:45][O:44][C:33]([O:43][CH3:14])([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:35]=1)[C:9]([C:1]1[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: C=CC(=O)O
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(=O)OCCOC(=O)c1ccccc1C(=O)[O-]
Agent: CCC(CO)(CO)CO
Solvent: COC(=O)c1ccccc1C(=O)OC
Product: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 472.6 %

Procedure:
Isotactic polymethyl methacrylate (1.0 g), syndiotactic polymethyl methacrylate (3.0 g) and hydroquinone (0.03 g) were dissolved in a mixture of dimethyl phthalate (6.81 g), trimethylolpropane triacrylate (1.59 g) and HOA-MPL 2-acryloxyethyl phthalate (14.30 g), a product from Kyoeisha Oil and Fats K.K.) and heated to 120° C. After a clear sol was obtained 2,2-dimethyloxy-2-phenyl acetophenone (0.33 g) was added to the sol. The sol thus obtained was cast onto a 50 μm-thick polyester sheet and cooled at -5° C. for one hour to give a photocurable self-retainable gelled sheet having a thickness of 5 mm.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:1][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: CC(C)n1nccc1-c1cnccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2ccncc2-c2ccnn2C(C)C)cn1
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (79 mg, 0.52 mmol, 1.5 eq.), 4-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (crude above, 0.35 mmol), and K2CO3 (145 mg, 1.05 mmol, 3 eq.) in DMF (10.0 mL) was heated at 100° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on RP-HPLC (Gemini 21.2×150 mm) twice using a mixture of CH3CN/water (0.1% HCOOH) as eluent to give 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (6.0 mg, 5%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 7.52 (d, J=1.7 Hz, 1H), 6.96 (s, 1H), 6.15 (d, J=1.8 Hz, 1H), 4.87 (s, 2H), 4.06 (sep, J=6.6 Hz, 1H), 3.75 (s, 3H), 1.31 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 353.1.
Reaction SMILES: [C:1](NCC(O)=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/C=C\CCCCCCCC.N[C@H](C(O)=O)C.N(CC(O)=O)C.[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44]>>[C:1]([CH:42]([CH2:41][CH2:40][CH2:39][CH2:38][NH2:37])[C:43]([OH:45])=[O:44])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(=O)O
Reactant: NCCCCCC(=O)O
Agent: CNCC(=O)O
Agent: C[C@H](N)C(=O)O
Product: CCCCCCCC(=O)C(CCCCN)C(=O)O

Procedure:
oleoylglycine, -alanine, -sarcosine and -6-aminocaproic acid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=[O:5])[C:2]([CH3:4])=[CH2:3].COC1C=CC(O)=CC=1.[Cl:24][SiH:25]([Cl:27])[Cl:26]>O1CCCC1.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Cl-].[Pt+4]>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Si:25]([Cl:27])([Cl:26])[Cl:24])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCCCCCCOC(=O)C(=C)C
Reactant: Cl[SiH](Cl)Cl
Agent: [Pt+4]
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)OCCCCCCCC[Si](Cl)(Cl)Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A reaction vessel fitted with a stirrer was charged with 50 g of 7-octenyl methacrylate, 250 mg of hydroquinone monomethyl ether and 1.5 cc of 1% chloroplatinic acid hexahydrate solution in tetrahydrofuran, and the mixture was heated to 40° C. To the mixture was added gradually 42 g of trichlorosilane with stirring, while the temperature of the mixture was kept at 45° C. or below. After the addition, the mixture was heated to 60° C. and reaction was conducted at this temperature for 1 hour to obtain 8-methacryloyloxyoctyltrichlorosilane.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:41]3[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (100 mg, 0.17 mmol) was treated as described in general procedure G using 4-trifluoromethylphenylboronic acid to provide 5-{4-[4-(2,4-dichloro-phenyl)-2-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([O:19]CC2C=CC(OC)=CC=2)=[O:18])[CH3:16])[N:13]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])[C:12]1=[O:43])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[N:13]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[O:31])[C:12]1=[O:43])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2].[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[N:13]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[O:31])[C:12]1=[O:43])[CH3:10]
Reactant: COc1ccc(COC(=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N2CC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1[C@@H](C)C(=O)O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1[C@@H](C)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-p-methoxybenzyloxycarbonylethyl]-1-(p-nitrobenzyloxycarbonylmethyl)azetidin-2-one (142 mg) in dry methylene chloride, there was BF3 -Et2O complex (163 mg) under ice-cooling, followed by stirring at room temperature. The reaction mixture was poured into a cold aqueous sodium bicarbonate solution, acidified with dilute hydrochloric acid and extracted with ethyl acetate three times. The organic layer was washed successively with dilute hydrochloric acid and brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-1-(p-nitrobenzyloxycarbonylmethyl)azetidin-2-one (Compound A) and (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-carboxyethyl]-1-(p-nitrobenzyloxycarbonylmethyl)azetidin-2-one (Compound B).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:29][CH3:30])[CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH2:27][I:28])(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[I-:28].[CH2:1]([S:17][CH2:18][CH:19]([O:29][CH3:30])[CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH2:27][C:32]1[S:31][CH:35]=[CH:34][NH+:33]=1)(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: c1cscn1
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCc1[nH+]ccs1)OC
Product: [I-]
Yield: 56 %

Procedure:
A solution of 600 mg (1.04 mM) of 1-hexadecylthio-3-(3-iodopropylsulfonylamino)-2-methoxypropane IIa2 in 5 ml of thiazole is stirred at 60° C. for 6 hours. After thiazole is evaporated, the residue is washed with ether and recrystallized from acetone to give 387 mg (0.584 mM) of 1-hexadecylthio-2-methoxy-3-(3-thiazoliopropylsulfonylamino)propane iodide Ia9 in 56% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:20][CH2:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:21][C:22]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=3)[N:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:23]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a stirred solution of 6-chloronicotinic acid (183 mg, 1.16 mmol) and N,N-diisopropylethylamine (409 mg, 552 μL, 3.16 mmol) in methylene chloride was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphonate (BOP) (559 mg, 1.26 mmol). After 15 min., 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (300 mg, 1.05 mmol) was added. After 1.5 hr., the suspension was diluted with CH2Cl2 and washed with water followed by citric acid solution (5%) and finally potassium carbonate solution. The organic layer was dried, filtered and concentrated to afford 6-chloro-N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-nicotinamide (340 mg, 76%). The product was used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1([CH3:19])[CH2:12][C:11](=O)[C:10]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:9]=2[O:8]1)[CH3:2].B(F)(F)F.CCOCC.B.C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1([CH3:19])[CH2:12][CH2:11][C:10]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:9]=2[O:8]1)[CH3:2]
Reactant: CCOC(=O)CCC1(C)CC(=O)c2ccc(O)cc2O1
Agent: B
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCC1(C)CCc2ccc(O)cc2O1
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
To a stirred solution of 1.5 g of racemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 ml of dry tetrahydrofuran, with ice bath cooling, was added 1.4 ml of boron trifluoride etherate, over a period of 2 minutes. The mixture was stirred at 0°-5° C. for 5 minutes whereupon 5.4 ml of 1M borane in tetrahydrofuran was added. Stirring was continued at 0°-5° C. for 2.5 hours then the mixture was decomposed by the addition of glacial acetic acid. Solvents were removed in vacuo then the residue was dissolved in methylene chloride. The solution was washed with sodium bicarbonate solution and brine, then dried, filtered and concentrated under reduced pressure. The residual orange oil (1.4 g) was chromatographed on 50 g of silica gel. Elution with 4:1 hexane-ethyl acetate afforded 0.9 g (63.1%) of racemic-3,4-dihydro-7-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a colorless oil.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[N:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)[CH:12]=1)=[O:7])C.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[C:22]1([C@@H:20]([NH:19][C:15]2[N:14]=[C:13]([N:11]3[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[C:10]3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[CH:18]=[CH:17][N:16]=2)[CH3:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cn(-c2ccnc(N[C@@H](C)c3ccccc3)n2)c(-c2cccc(C(F)(F)F)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1nccc(-n2cc(C(=O)O)nc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 60 °C
Yield: 88.7 %

Procedure:
LiOH (3.75 g, 0.1566 mol) dissolved in a minimum amount of water was added to (S)-1-[2-(1-phenylethylamino)pyrimidin-4-yl]-2-(3-trifluoromethylphenyl)-1H-imidazole-4-carboxylic acid ethyl ester (4.2 g, 0.0087 mol) in 20 mL THF. 3 mL MeOH was added and the solution warmed to 60° C. for 45 min. After cooling to room temperature, the reaction was acidified with pH 4.5 citric acid solution (buffered with NaOH) and extracted with ethyl acetate (2×150 mL). The ethyl acetate was dried over anhydrous magnesium sulfate and concentrated to give 3.5 g of a solid. The solid was stirred vigorously for 30 minutes as a slurry in Et2O and filtered to give the title compound (2.5 g ) as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]([CH2:12][C:13](OCOC)=[O:14])[C:6](OCOC)=[O:7].CSC.B.CO>O1CCCC1>[OH:7][CH2:6][C@@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:12][CH2:13][OH:14]
Reactant: COCOC(=O)C[C@H](OCOC)C(=O)OCOC
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: COCO[C@H](CO)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
A solution of (S)-2-methoxymethoxybutanedioic acid, bis methoxymethyl ester (10 g, 37.5 mmol) in dry tetrahydrofuran (10 ml) under dry nitrogen was treated with borane dimethylsulphide (8.3 ml, 83 mmol). The solution was heated between 60° C. and 80° C. over a period of 5.5 hours and then cooled in ice and treated dropwise with methanol (50 ml). After effervescence had ceased the solution was stirred at room temperature for 18 hours and the solvent removed under vacuum. The residue was evaporated to dryness with methanol (2×50 ml) and the residue chromatographed on silica, eluting with chloroform-methanol 5:1 to give (S)-1,4-dihydroxy-2-(methoxymethoxy)butane (3.9 g, 69%); IR: υmax (film) 3400, 2940, 2890, 2820, 1470, 1440, 1410, 1380, 1300, 1210, 1150, 1100, 1030, 920 cm-1 ; 1H NMR: δH (CDCl3) 1.78 (2H, m, CH2), 2.96 (2H, s, D2O exchangeable OH's), 3.44 (3H, s, OCH3), 3.5-3.85 (5H, m, CH plus 2×CH2 's), 4.72 (1H, d, J=7 Hz, CH of CH2), 4.77 (1H, d, J=7 Hz, CH of CH2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[F:36][CH:37]([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:13])=[O:14])[CH2:38][CH:37]([F:47])[F:36])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1nccnc1N(CC(F)F)S(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 44 h
Yield: 75 %

Procedure:
To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (1.5 g) in acetonitrile (15 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (1.2 g) in acetonitrile (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 44 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane) to give 3-[(2-chloro-5-trifluoromethyl-phenylmethanesulfonyl)-(2,2-difluoro-ethyl)-amino]-pyrazine-2-carboxylic acid methyl ester as a light yellow solid (1.300 g). 1H-NMR (400 MHz, CDCl3): 8.63 (s, 1H), 8.53 (s, 1H), 7.76 (m, 1H), 7.53-7.59 (m, 2H), 6.15 (tt, 1H), 4.69 (s, 2H), 4.23-4.31 (m, 2H), 4.02 (s, 3H) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH:2]=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:4][CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-(bromomethyl)benzoate (458 mg, 2 mmol) was added to dry toluene (8 mL) along with triphenylphosphine (609 mg, 2.2 mmol). Under nitrogen, reflux conditions were applied for three hours and the mixture was then permitted to cool to room temperature. The fine white solid was filtered off, washed thoroughly with EtOAc, and dried under vacuum (967 mg). This solid was stirred in dry THF (4 mL) under nitrogen, and potassium t-butoxide (246 mg, 2.18 mmol) was added. The bright orange mixture was heated under reflux for one hour. Upon cooling, benzaldehyde (202 μL, 212 mg, 1.2 mmol) in dry THF (2 mL) was added. Further heating under reflux was applied for thirty minutes. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by flash chromatography on SiO2 using EtOAc/hexanes 10:90. A white solid was obtained (97 mg, 20%).