Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][OH:3].C[Na].[CH2:8]([O:10][CH:11]([O:18][CH2:19][CH3:20])/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH3:9].O>CS(C)=O>[CH2:19]([O:18][CH:11]([O:10][CH2:8][CH3:9])[CH:12]1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:2](=[O:3])[CH2:1][O:4]1)[CH3:20]
Reactant: O=C(O)CO
Reactant: CCOC(/C=C/C(=O)OC)OCC
Agent: C[Na]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(OCC)C1OCC(=O)C1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: To the suspension of 7.15 g of methyl sodium glycolate in 50 ml of dimethylsulfoxide and 25 ml of diemthylformamide, cooled to 0°, are added at once 9.5 g of methyl 4,4-diethoxy-crotonate and the mixture is stirred at room temperature for 3 hours. It is poured into water, washed with diethyl ether and the aqueous layer is acidified with cold N hydrochloric acid. It is extracted twice with diethyl ether, the extract dried, evaporated and the residue distilled, to yield the methyl 2-diethoxymethyl-4-oxo-tetrahydrofuran-3-carboxylate boiling at 123°-126°/0.5 mm Hg.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C:12]1[CH2:11][CH2:10][C@@H:9]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:7]2=1)(=[O:3])[CH3:2].CO[CH:33](OC)[N:34](C)C.Cl.NO>O1CCOCC1.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:13]1[C:12]2[CH2:11][CH2:10][C@@H:9]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([C:1]1[O:3][N:34]=[CH:33][CH:2]=1)[CH:5]=2
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C(C)C)C1
Agent: Cl
Agent: NO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(-c4ccno4)ccc3n2Cc2cccc(F)c2)C1
Temperature: 40 °C

Procedure:
Combine (R)-N-[6-Acetyl-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 191) (0.055 g, 0.14 mmol) and dimethylformamide dimethylacetal (0.81 g, 6.8 mmol) and heat at 100° C. for 82 h. Concentrate in vacuo and treat the resulting residue with hydroxylamine hydrochloride (0.012 g, 0.18 mmol) in dioxane at 23° C. for 1 h before warming to 40° C. briefly. Dilute with water and collect 0.029 g of a solid by filtration. Recrystallize from EtOAc/hexanes to yield a light yellow solid. mp: 238-241° C.; MS (ES): m/z 432 (M+1); HPLC: Rt=2.59 (85%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.N#N.Br[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[C:17]#[N:18]>C1(C)C=CC=CC=1.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:17]([C:16]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=1[C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)#[N:18]
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: N#Cc1cc(F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(F)cc2C#N)cc1
Temperature: 25 °C

Procedure:
A solution of p-tolyltrimethyltin (1.26 g; 4.96 mmol) in dry toluene (8 mL) was degassed with a stream of N2 for ca. 5 min. To this solution under N2 was added 2-bromo-5-fluorobenzonitrile (0.901 g; 4.51 mmol) and Pd(PPh3)4 (260 mg; 5 mol%). The reaction was stirred at reflux under N2 for 12 hr and then cooled to room temperature. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The product was purified by flash chromatography on a silica gel column, eluting with Hex/CH2Cl2 to afford the title compound as a slightly yellow solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[Na+].I[CH2:18][CH:19]([OH:22])[CH2:20][OH:21].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCNc1ccc(CC(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.34 g. of 4-(allylamino)phenylacetic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(allylamino)phenylacetate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1)([OH:3])=[O:2].[CH3:25]O.OS(O)(=O)=O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1)([O:3][CH3:25])=[O:2]
Reactant: CO
Reactant: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1ccnc2ccccc12
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Yield: 90 %

Procedure:
A solution of 5-carboxy-3-(quinol-4-ylmethylene)-2-oxindole (3.163 g, 10 mmol), methanol (3.2 g, 100 mmol) and H2SO4 95% (1 g) in benzene (100 ml) was heated in a Soxhlet apparatus for 10 h. To dry the distillate continuously, the cap of the Soxhlet contained anhydrous MgSO4. After cooling, water was added, the organic phase repeatedly washed with water and then evaporated under vacuum. Thus almost pure title compound was obtained in about 90% yield.
Reaction SMILES: [OH-].[Na+].[Si:3]([O:20][CH2:21][C@H:22](O)[CH2:23][CH2:24][C:25]([OH:27])=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(OC)(OC)(=O)=O.[Si](OC[C@@H](I)CCC(O)=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.II.[C:88]([O-:91])(=[S:90])[CH3:89]>C(O)C.CS(C)=O.C1(C)C=CC=CC=1>[C:88]([S:90][C@@H:22]([CH2:21][O:20][Si:3]([C:16]([CH3:17])([CH3:19])[CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:91])[CH3:89]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[Si](OC[C@H](O)CCC(=O)O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Si](OC[C@@H](I)CCC(=O)O)(c1ccccc1)c1ccccc1
Agent: II
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)S[C@H](CCC(=O)O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
D-glutamic acid (1) was treated with sodium nitrite in hydrochloric acid to produce (R)-1,4-butyrolactone-4-carboxylic acid (2). Compound 2 was then reduced by borane-dimethyl sulfide complex in THF to give the corresponding (R)-4-(hydroxymethyl)-4-butyrolactone (4), which was subsequently treated with tert-butyldiphenylsilyl chloride in methylene chloride using imidazole as a catalyst to afford (R)-5-O-tert-butyldiphenylsilyl-4-hydroxymethyl-1,4-butyrolactone (53). The protected lactone 53 was opened with sodium hydroxide in ethanol and then converted to the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(R)-hydroxypentanoic acid (54) by reaction with dimethyl sulfate in dimethyl sulfoxide. Commpound 54 was transformed into the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(S)-iodopentanoic acid (55) by treatment with triphenylphosphine, imidazole and iodine. Displacement of the iodo group in compound 55 by thioacetate in toluene occurred readily to give the methyl ester of 4-(R)-(acetylthio)-5-[(tert-butyldiphenylsilyl)oxy]pentanoic acid (56). Compound 56 was then treated with 2 equivalents of diisobutylaluminum hydride (DIBAL) in toluene to reductively deprotect the sulfur and reduce the methyl ester to an aldehyde, thereby producing the thiolactol via spontaneous cyclization. The thiolactol was acetylated with acetic anhydride in pyridine to give 1-o-acetyl-5-o-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (57): 1HNMR (CDCl3) delta 7.67 (m, 4H, ArH), 7.40 (m, 6H, ArH), 6.10 (m, 1H, 1-H), 3.70 (m, 1H, 4-H), 3.52 (m, 2H, 5-H), 2.20 (m, 2H, CH2), 2.00 (2 s, 3H, CH3CO--), 1.92 (m, 2H, CH2), 1.08 (s, 9H, tert-butyl).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[N:15][CH:16]=1.[F:19][C:20]([F:27])([F:26])[CH2:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH:18][S:22]([CH2:21][C:20]([F:27])([F:26])[F:19])(=[O:24])=[O:23])[CH:14]=[N:15][CH:16]=1
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccccc21
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: Cn1c(-c2cncc(CNS(=O)(=O)CC(F)(F)F)c2)cc2ccccc21

Procedure:
C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b) and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according to the method described in Example 186f to give 2,2,2-trifluoro-ethanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 3.78 (s, 3H), 4.23 (q, J=9.6 Hz, 2H), 4.44 (s, 2H), 6.66 (d, J=0.5 Hz, 1H), 7.06-7.12 (m, 1H), 7.23 (ddd, J=7.7, 1.1 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H). HRMS (ESI) m/z 384.0999 [(M+H)+ Calcd for C17H17F3N3O2S: 384.0994].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Solvent: O
Solvent: Oc1ccccc1
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(F)cc23)CC1
Yield: 90.3 %

Procedure:
A mixture of 4.4 g (15 mmol) of 4-chloro-2-(4-chlorophenyl)-6-fluoroquinoline, 3.9 g (30 mmol) of isonipecotamide, and 6 g of phenol was stirred and heated in an oil bath at 165°-180° for 2 hr. It was then cooled and diluted with 100 ml of water. Crystallization was induced by scratching. The solid was collected and washed with ether to give 5.2 g of crude product, mp 258°-260° dec. Recrystallization from pyridine/water gave off-white needles, mp 259°-261°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH2:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[OH:16])[CH:7]=1.I[CH2:19]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:19][O:16][C:10]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=3[CH2:8][C:6]=2[CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1O
Reactant: ICI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)Cc1cc(Cl)ccc1OCO2
Temperature: 105 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of bis-(5-chloro-2-hydroxyphenyl)-methane (24.4 g, 90.7 mmol) in dry DMF (340 mL) was added diiodomethane (25.5 g, 95.0 mmol) and potassium carbonate (18.2 g, 132 mmol). The mixture was stirred at 105° C. for 16 h. The mixture was added to ice water (1200 mL) and stirred for 30 min. The product was isolated by filtration, and washed with water and suspended in a mixture of ethanol (200 mL) and 4N NaOH (50 mL). The mixture was heated at 80° C. for 1 h. The mixture was added to water (600 mL) and 21.45 g (84%) 2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin was isolated by filtration.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Li]CCCC.[I:20]I>C1COCC1>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([I:20])[CH:6]=1
Reactant: CC(C)(C)C#Cc1ccc(C(=O)O)s1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(I)c(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 5-(3,3-Dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (6.2 g, 30 mmol; see patent application U.S. Pat. No. 5,861,421) in THF (100 mL) was added a solution of nBuLi (2.0 M in pentane, 33 mL, 66 mmol) via an addition funnel at −78° C. After addition, the reaction was stirred at −78° C. for 1 h. A solution of I2 (7.7 g, 30 mmol) in THF (100 mL) was added slowly (ca. 15 min) to the flask. After a further 10 mins, the reaction was quenched with 1 N HCl (50 mL) and warmed to room temperature. The volatiles were removed in vacuo and the residue was dissolved in ether (500 mL). The organic solution was washed with 1 M Na2S2O3 (100 mL×2), brine (100 mL) and dried over Na2SO4. After concentrated in vacuo, the residue was purified by silica gel chromatography (EtOAc/hexanes) to give 5-(3,3-Dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid (5.9 g, 65%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[N:2].OO.NC(N)=[O:20].[OH-].[Na+]>CO>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)(=[O:20])[NH2:2]
Reactant: NC(N)=O
Reactant: COC(=O)c1ccc2c(C#N)n[nH]c2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1n[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of methyl 3-cyano-1H-indazole-6-carboxylate (254 mg, 1.26 mmol) in methanol (12 mL) at 0° C. was added a cold solution of urea hydrogen peroxide (1.22 g, 12.6 mmol) in sodium hydroxide (12.6 mL 1M in water, 12.6 mmol). The yellow solution was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove methanol. The pH of the resulting residue was adjusted to ˜4 with 1N hydrochloric acid. A precipitate formed. The mixture was filtered and the solid was dried to afford 3-carbamoyl-1H-indazole-6-carboxylic acid as a brown solid (82 mg, 32%). 1H NMR (400 MHz, DMSO-d6, δ): 13.84 (s, 1 H), 13.04 (br. s., 1 H), 8.20 (d, J=8.4 Hz, 1 H), 8.13-8.16 (m, 1 H), 7.77 (br. s., 1 H), 7.74 (dd, J=8.6, 1.4 Hz, 1 H), 7.38 (br. s., 1 H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:23](=[O:24])[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:33])=O)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+]>N1C=CC=CC=1>[CH2:25]([C:22]1([CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:33])=[C:14]([C:12]2[NH:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2](=[O:4])(=[O:3])[N:1]=2)[C:23]1=[O:24])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC1(CCCC)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of the product of Example 4G (298 mg, 0.63 mmol) and cesium carbonate (123 mg, 0.38 mmol) in pyridine (6 mL) was stirred at 140° C. for 18 hours, cooled to 25° C. and the pyridine removed by short path distillation under high vacuum (50° C./0.3 mm Hg). A suspension of the residue in ethyl acetate was treated with saturated ammonium chloride solution. The organic layer was washed with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate in hexane to afford the title compound (157 mg, 55%). 1H NMR (300 MHz, CDCl3): δ 16.71 (d, J=3.68 Hz, 1 H), 14.39 (s, 1 H), 14.24 (s, 1 H), 8.28 (d, J=8.09 Hz, 1 H), 7.99 (d, J=8.09 Hz, 1 H), 7.66 (m, 1 H), 7.46 (m, 1 H), 7.31 (m, 6 H), 2.30 (m, 2 H), 1.92 (m, 2 H), 1.16 (m, 3 H), 0.88 (m, 2 H), 0.62 (m, 7 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-:18].[Ca+2]>O1CCOCC1.O>[OH:18][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(CO)cc1
Yield: 87.8 %

Procedure:
To a suspension of 2 (6.0 g, 22 mmol) in a mixture of 1,4 dioxane (60 ml) and water (60 ml) was added calcium carbonate (10.8 g, 110 mmol). The mixture was heated to reflux for 18 h, concentrated in vacuo and the residue portioned between DCM and water. The organic layer was collected, dried over MgSO4, concentrated in vacuo then recrystalised from diethyl ether to furnish 3 (4.1 g, 89%) as a white solid; M.P. 59-61° C. (Lit 61-64° C.); δH (CDCl3) 3.14 (s, 1H, CH2OH), 4.75 (s, 2H, CH2OH), 7.41-7.49 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.54-7.58 (m, 1H, 4′-H), 7.72-7.76 (m, 4H, 2-, 2′-, 6-, 6′-H) ppm; δC (CDCl3) 64.4 (CH2OH), 126.4 (3′-, 5′-C), 128.3 (3-, 5-C), 130.0, 130.4 (2-, 2′-, 6-, 6′-C), 132.5 (4′-C), 136.4, 137.5 (1-, 1′-C), 140.0 (4-C), 196.9 (Ar2C═O) ppm; νmax (thin film) 3406, 3058, 2921, 1655, 1279 cm−1; m/z (ES) 211 ([M−H]− 100%), 183 (45%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16](O)[CH2:15][CH2:14]1>>[CH3:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14]1
Reactant: C[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@@H](C)CC1)C(C)=O

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (3.61 g) was reacted with trans-4-methylcyclohexanol as described in Example 4a, Method 3, to give the title compound as a colourless liquid (1.66 g, 29%).[Found: M+ +H, 256.1555. C13H21NO4 requires M+H, 256.1549]. νmax (film) 2930, 2850, 1745, 1690 cm-1 ; δH (CDCl3) 0.89 (3H, d), 1.20 (2H, m), 1.35 (3H, t), 1.47 (3H, m), 1.60 (2H, m), 2.03 (2H, m), 2.40 (3H, s), 4.36 (2H, q), 4.51 (1H, m); δC (CDCl3) 14.3, 22.2, 25.1, 29.1 (2C), 29.4 (2C}, 31.5, 61.8, 81.2, 150.2, 161.5, 193.1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](I)[CH3:8].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][NH:21][CH2:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.CN(C)C=O>O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][N:21]([CH2:7][CH3:8])[CH2:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCI
Reactant: COc1cccc(C2=CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 16 h

Procedure:
9.8 g of sodium carbonate and 2.6 ml of ethyl iodide were added to a suspension of 7 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride and 70 ml of dimethylformamide and the mixture was stirred for 16 hours and was diluted with water. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture to obtain 5.3 g of 3-(3-methoxyphenyl)-1-ethyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:26]=[C:27]([S:31]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[CH2:74][C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]([F:85])([F:84])[F:83])=[O:76]>CN(C=O)C>[O:76]=[C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]([F:85])([F:83])[F:84])[CH2:74][O:38][C:37](=[O:39])[CH2:36][CH2:35][NH:34][S:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:15]3([NH:14]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:16]3)[CH2:18][CH2:19]2)=[O:24])[CH:26]=1)(=[O:32])=[O:33]
Reactant: O=C(CO)N1CCCC1C(F)(F)F
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCCC(=O)O)c4)CC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCCC(=O)OCC(=O)N5CCCC5C(F)(F)F)c4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid (step 2) (400 mg, 0.690 mmol) and N,N-diisopropylethylamine (357 mg, 2.76 mmol) in DMF (4 ml) was added HATU (262 mg, 0.690 mmol). The solution was stirred at RT for 15 min, after which time 2-hydroxy-1-(2-(trifluoromethyl)pyrrolidin-1-yl)ethanone (Int. D) (262 mg, 0.690 mmol) in DMF (2 ml) was added. The resulting solution was stirred at RT for 6 days, after which time it was poured onto water (10 ml). A white precipitate formed which was collected by filtration, and washed with iso-hexane (20 ml), and purified by C18 reverse phase chromatography eluting with MeCN/water/0.1% TFA to afford the title product; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (1H, s), 9.37 (1H, s), 9.02 (1H, s), 7.92-7.29 (4H, m), 7.24 (14N, s) 7.12 (14N, s), 6.96 (14N, s), 4.95-3.90 (11H, m), 3.66 (2H, t), 3.41 (2H, t), 3.35 (2H, m), 3.07 (2H, t) 2.20-1.61 (7H, m); LC-MS Rt 0.91 mins; 759.0 [M+H]+, Method 2minLC_v003.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1 g of methyl 2-chloro-6-methylpyrimidine-4-carboxylate, 20 mL of methanol and 2 mL of 30% sodium methoxide in methanol was stirred under nitrogen at room temperature for 3 hrs, quenched with 3 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 25 mL of saturated sodium bicarbonate and 3×20 mL of ethyl acetate and the extracts dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1)=183.1; 1H NMR (400 MHz, CDCl3) 7.5 (s, 1H), 4.1 (s, 3H), 4.0 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.C1CCCCC1.[Li]C(CC)C.C[O:24][B:25](OC)[O:26]C>C1COCC1>[F:11][C:2]1([F:1])[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([B:25]([OH:26])[OH:24])[C:5]=2[O:6]1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: COB(OC)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OB(O)c1cccc2c1OC(F)(F)O2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2,2-Difluoro-1,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to −78° C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at −78° C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to −30° C. The reaction mixture was quenched with a 2N solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification.