Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1([C:13]2[S:14][C:15]([C:18]3[CH:19]=[C:20]([N:33]([C:41]4[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][N:42]=4)C(=O)OC(C)(C)C)[CH:21]=[C:22]([NH:24][C:25](=[O:32])[NH:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:23]=3)=[CH:16][N:17]=2)[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[CH:27]1([NH:26][C:25]([NH:24][C:22]2[CH:21]=[C:20]([NH:33][C:41]3[N:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][N:42]=3)[CH:19]=[C:18]([C:15]3[S:14][C:13]([C:9]4([OH:8])[CH2:10][CH2:11][CH2:12]4)=[N:17][CH:16]=3)[CH:23]=2)=[O:32])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N(c1cc(NC(=O)NC2CCCC2)cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)c1)c1nccc(C(F)(F)F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC3)s2)c1)NC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To a solution of the product of Step 3 (56 mg, 0.076 mmol) in dichloromethane (1 mL) was added TFA (1 mL) and the mixture was stirred for 60 minutes at room temperature. The mixture was concentrated in vacuo, then the residue was diluted with ethyl acetate (30 mL) and washed with sat. NaHCO3(aq) (30 mL) and brine (30 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in THF (1 mL), TBAF (228 μL, 1.0 M; 0.228 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, and the residue purified by chromatography on silica gel (100:0 to 80:20, ethyl acetate: EtOH) provided 9 mg (0.017 mmol, 28%) of the desired 1-cyclopentyl-3-(3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)urea as a white solid. MS APCI: [M+H]+ m/z 519.1. 1H NMR (400 MHz, d6-acetone): δ 9.22 (s, 1H); 8.81 (d, J=4.9 Hz, 1H); 8.00-7.90 (m, 3H); 7.78 (s, 1H); 7.66 (s, 1H); 7.23 (d, J=4.9 Hz, 1H); 5.90 (d, J=7.0 Hz, 1H); 5.49 (s, 1H); 4.17-4.08 (m, 1H); 2.79-2.59 (m, 2H); 2.49-2.37 (m, 2H); 2.06-1.88 (m, 4H); 1.82-1.48 (m, 4H); 1.51-1.42 (m, 2H). rhSYK activity=+++
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[C:12]([F:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[F:15])#[N:2].B.[H][H].Cl>O1CCCC1.CO>[NH2:2][CH2:1][CH2:3][C:4]1[CH:13]=[C:12]([F:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[F:15]
Reactant: [H][H]
Reactant: N#CCc1cc(F)c2c(c1F)OCCO2
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1cc(F)c2c(c1F)OCCO2

Procedure:
6-Cyanomethyl-5,8-difluoro-1,4-benzodioxane (30.34 g, 0.158 mole) dissolved in 300 ml of dry tetrahydrofuran is treated with 308 ml of 1 M borane in tetrahydrofuran under nitrogen. After 2 hours of reflux 300 ml of methanol is added continuously (hydrogen evolution occurs, vigorously at first), then the mixture is refluxed for 30 minutes. Then 50 ml of 10% hydrochloric acid is added very carefully (hydrogen gas evolution again) and the mixture refluxed another 30 minutes. The reaction mixture is concentrated under vacuum to a small volume, then 300 ml of water is added and the mixture made basic with 40% sodium hydroxide. This is extracted with ether, dried, and concentrated to give 6-(2-aminoethyl)-5,8-difluoro-1,4-benzodioxane.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([CH3:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].FC(F)(F)C(C1C=CC(OC)=C(C=1)[CH:30]=[O:31])C(F)(F)F>>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH:11]=1)[CH:30]=[O:31])([CH3:1])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Reactant: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1
Product: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 57 in the same manner of Compound 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[N:10]=1)[C:5]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:7]
Reactant: NC1CC1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (1 eq.) in DMF (0.05 M) was added sequentially cyclopropylamine (1.05 eq.), Hunig's base (3 eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting solution was stirred at RT for 4 h. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 10:1 (v/v) CH2Cl2:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1)=[O:8].[CH3:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:22][CH3:21])[N:14]=1)=[O:8]
Reactant: CN
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Product: CNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea and excess methylamine (2.0 M solution in tetrahydrofuran) was heated for 15 minutes at 60° C. under microwave irradiation. The volatiles were removed in vacuo and the product was purified by column chromatography (DCM/0-15% NH3 saturated MeOH) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@@H:13]([CH2:18][OH:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].I[CH2:27][CH3:28]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:27][CH3:28])[C@@H:13]([CH2:18][OH:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(F)c(F)c1
Temperature: 50 °C
Yield: 90 %

Procedure:
A solution of 2G (2.85 g, 8.8 mmol) in DMF (20 mL) was added with an. K2CO3 (1.5 mol eq, 1.83 g) and, after few minutes, 2-iodoethane (1.2 mol eq, 1.09 mL) was added and the mixture heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (150 mL) and the aqueous phase extracted with EtOAc (3×60 mL). The recombined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 3G as a pale yellow oil (2.8 g, 90% yield). 1HNMR (DMSO, 200 MHz) δ 1.15 (m, 3H), 1.98 (s, 3H), 3.08 (m, 2H), 4.04 (q, 2H, J=8), 4.58 (t, 1H), 5.15 (bm, 1H), 7.71 (m, 2H), 7.94 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[C:10]#[C:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1>CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[C:9](=[O:13])[C:10]#[C:11][CH3:12])[CH:24]=1
Reactant: CC#CC(=O)Nc1ccccc1I
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#CC(=O)N(Cc1cccc(C(=O)OC)c1)c1ccccc1I
Reaction time: 0.17 h

Procedure:
A mixture of but-2-ynoic acid (2-iodo-phenyl)-amide (2.85 g, 10 mmol) and cesium carbonate (4.89 g, 15 mmol) in DMF (20 ml) was stirred for 10 minutes. 3-bromomethyl-benzoic acid methyl ester (2.52 g, 11 mmol) was added. Then the mixture was stirred for 12 hours at room temperature. After removal of solids, the filtrate was treated with water and extracted with ether. The organic layer was dried over sodium sulfate and concentrated to give the residue which was purified by flash chromatography, eluting with ethyl acetate/hexane=1:4 to afford the product 3-{[(2-iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid methyl ester as yellow solid (3.03, 70%). MS calcd. for C19H16INO3 433.3, obsd. (ESI+) [(M+H)+] 434.1.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>ClCCl>[C:13]([NH:12][C@@H:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:1]1[CH:6]=[CH:5][C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:3][CH:2]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)NC1CCCC1c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCC[C@H]1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C

Procedure:
4.7 g of the crude product of example 2a were dissolved in 90 ml of dichloromethane. To this mixture 5.4 ml of chloro sulfonic acid were added drop by drop under stirring at room temperature. The reaction mixture was heated at 50° C. for 1 hour and, after cooling to room temperature, triturated with 70 ml of ice water. After separating the organic layer was dried over sodium sulfate and evaporated to dryness yielding 4.4 g of the crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([CH2:33][OH:34])=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:41][CH2:42][CH2:43][CH2:44]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:44][CH2:43][CH2:42][Br:41])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([CH2:33][OH:34])=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[N:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a suspension of 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [1.45 g, 2.99 mmol, Intermediate (76)] in 1,3 dibromopropane (5 mL) was added cesium carbonate (2.43 g, 7.48 mmol). The suspension was stirred at 80° C. for 3 hours. It was allowed to cool down to room temperature. The insoluble was filtered off. The filtrate was loaded on silica gel for chromatography (n-heptane/ethyl acetate, 100/0 then gradually to 65/35 as eluant) to produce 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [990 mg, 55%, Intermediate (77)]. LC/MS: 606.1 (M+H), RT=3.22 minutes.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CC[O:8][CH2:9][CH3:10]>[Cl-].[Zn+2].[Cl-]>[CH2:9]([OH:8])[CH2:10][CH2:4][CH2:3]/[CH:2]=[CH:1]/[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCC/C=C/CCCCO

Procedure:
FIG. 16 shows a synthesis of 5-decenyl acetate which involves the cross-metathesis of vinyl borate pinacol ester (Matheson, D. S J Am Chem Soc (1960) 82, 4228-4233) with 5-hexenol THP ether (or 1,10-diTHP ether of 5-decene) with Catalyst 823 to yield a pinacol ester of 1-borohexen-6-ol THP ether. This product was coupled with butyl lithium and zinc chloride under Suzuki conditions as described by Miycuira (Org Syn VIII p 532) to yield E-5-decenol THP ether in a 91:9 E:Z isomeric ratio. This material was purified by column chromatography and then acetated to yield 5-decenyl acetate in 91:9 E:Z isomeric ratio.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Li])=[C:21]([O:26][CH3:27])[C:20]=1[O:28][CH3:29]>>[OH:13][C:9]1([C:23]2[CH:22]=[C:21]([O:26][CH3:27])[C:20]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:24]=2)[C:10]2[C:5](=[C:4]([N+:14]([O-:16])=[O:15])[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: [Li]c1ccc(OC)c(OC)c1OC
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Product: COc1cc(C2(O)CCCc3c2ccc(OC)c3[N+](=O)[O-])cc(OC)c1OC
Reaction time: 2 h
Yield: 55 %

Procedure:
6-Methoxy-5-nitro-1-tetralone (21) (2.65 g, 12.0 mol) was added at −20° C. to the trimethoxyphenyllithium and stirring was continued for 2 h (−20° C. -RT). The mixture was partitioned between CH2Cl2 and water, the organic layer was dried over anhydrous sodium sulfate, and, after filtration, the organic layer was concentrated in vacuo, to afford 1-Hydroxy-6-methoxy-5-nitro-1-(3′,4′,5′-trimethoxyphenyl)tetralin (30) as a crude yellow oil. (GC-MS shows the yield is about 55%). This compound, without purification, was added to a refluxing mixture of acetic acid (10 mL) and water (80 mL), and iron (0.5 g) was added. After heating at reflux for 1 h, the mixture was partitioned between CH2Cl2 (3×100 mL) and water (100 mL). The organic layer was washed with NaHCO3 (sat.) and water (100 mL each), dried over anhydrous sodium sulfate, and, after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. Purification by column chromatography afforded 5-Amino-6-methoxy-1-(3′,4′,5′-trimethoxyphenyl)-3,4-dihydronaphthalene (31):
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Combine 4-hydroxy-3-methyl-benzaldehyde (0.502 g, 3.69 mmol), 6-chloro-nicotinonitrile (0.510 g, 3.68 mmol), and potassium carbonate (1.28 g, 9.26 mmol) in dimethylacetamide (18 mL) and warm to 100° C. After 1 h. cool to ambient temperature, dilute reaction mixture with water (40 mL), and extract with ethyl acetate (3×50 mL). Wash combined organic extracts with water and brine successively, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes→ethyl acetate gradient/1.5 L) to provide 0.784 g (89%) of the title compound as a light brown solid: mass spectrum (electrospray): m/z=239.0 (M+1); 1H NMR (CDCl3): 10.01 (s, 1H), 8.44 (d, 1H, J=2.4 Hz), 7.99 (dd, 1H, J=2.0, 8.3 Hz), 7.86 (s, 1H), 7.81 (dd, 1H, J=1.5, 8.3 Hz), 7.23 (d, 1H, J=8.3 Hz), 7.13 (d, 1H, J=8.8 Hz), 2.25 (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([N:16]1[C:20]2=[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:22]=[N:23][CH:24]=[C:19]2[C:18]([CH3:34])=[C:17]1[CH3:35])[CH:13]=[CH:14][CH3:15]>ClCCl>[CH2:12]([N:16]1[C:20]2=[C:21]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[N:22]=[N+:23]([O-:6])[CH:24]=[C:19]2[C:18]([CH3:34])=[C:17]1[CH3:35])[CH:13]=[CH:14][CH3:15]
Reactant: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC=CCn1c(C)c(C)c2c[n+]([O-])nc(OCc3ccc(F)cc3)c21
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
A solution of 0.72 g (0.0029 mole) of m-chloroperoxybenzoic acid (purity: 700%) in 20 ml of dichloromethane was added to a solution of 0.72 g (0.0029 mole) of 1-(2-butenyl)-7-(4-fluorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine in 70 ml of dichloromethane at room temperature and the resulting mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was washed three times with 40 ml each of a saturated aqueous solution of sodium hydrogencarbonate. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 100:1 to 100:4 mixture of chloroform and methanol as an eluent to give crystals, which were washed with a mixture of ether and hexane to give 0.63 g of the title compound (cis/trans=27/73) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:19]([N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=2[OH:23])[CH2:29]1)=[O:20]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccc(F)cc13)C2
Yield: 29.6 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 97 (29.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.66 and 2.91 (2t, 2H), 3.52 and 4.02 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.44 and 4.90 (2s, 2H), 6.32-6.92 (m, 2H), 7.40-7.46 (m, 1H), 7.61-7.78 (m, 2H), 8.03-8.10 (m, 1H), 8.15-8.38 (m, 3H), 8.69 and 8.73 (2s, 1H); MS (ESI) m/z 448 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:14]1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Yield: 50.7 %

Procedure:
4-Fluoro-3-nitrobenzonitrile (0.5 g, 3.0 mmol), 2-morpholinoethanol (0.37 mL, 3.0 mmol), and potassium carbonate (0.42 g, 3.0 mmol) in DMSO (2 mL) were heated at 50° C. for 16 hours. Water (10 mL) was added to the reaction mixture, and the solid was collected via filtration. The solid was washed with water (3×2 mL) to afford Intermediate 27A (422 mg, 50.6% yield) as a tan solid. HPLC: Rt=0.78 min. (PHENOMENEX® S5 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=278.16 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH:7]1[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:14][CH2:13][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3])[O:6]1)(=[O:4])=[O:3]
Reactant: OCC1CCC(CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC(COS(C)(=O)=O)O1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
Methanesulphonyl chloride (307.8 g, 2.7 mol) is added dropwise to a solution of tetrahydrofuran-2,5-dimethanol (118.8 g, 900 mmol) and of triethylamine (454.5 g, 4500 mmol) in 1.54 L of dichloromethane at 0° C. The reaction medium is maintained at 0° C. for 1 hour, ice-cold water is then added and the organic phase is separated out and washed with 500 mL of dilute (1 M) hydrochloric acid solution. The organic phase is separated out and then washed with 500 mL of saturated aqueous NaHCO3 solution. The organic phase is finally separated out and concentrated to give 236.7 g of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate in the form of a brown oil in a purity equal to 96% (determined by LCMS). Reaction yield: 91.0%. A solution of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate (236.7 g, 821.7 mmol) and NaN3 (270.0 g, 4.1094 mol) in DMSO (1.350 L) is heated at 95° C. and stirred overnight. The reaction medium is added to ice-cold water and extracted with 3 times 700 mL of ethyl acetate. The extracts (phase containing ethyl acetate) are successively washed with water, saturated aqueous NaHCO3 solution and dried overnight on MgSO4 and then filtered to remove the MgSO4. The phase containing the ethyl acetate is concentrated to give 166.5 g of 2,5-bis(azidomethyl)tetrahydrofuran in the form of a brown oil. A mixture of 2,5-bis(azidomethyl)tetrahydrofuran (166.5 g) and of Pd-C (10%, 10.8 g) in methanol (2.7 L) is stirred overnight at room temperature under 1 atm of H2. The reaction medium is filtered and the filtrate is concentrated under vacuum to give 90.0 g of 2,5-bis(aminomethyl)tetrahydrofuran in the form of a yellow oil. The total yield for the 3 successive reactions is 75%. The process for synthesizing 2,5-bis(aminomethyl)tetrahydrofuran gives a 90/10 mixture of the cis/trans isomers according to 13C NMR analysis in deuterated methanol.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[C:20]([NH2:28])(=[NH:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[C:11]1([C:10]2[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:28]=[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:27]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Reactant: N=C(N)c1ccncc1
Agent: Cl
Product: O=C(O)c1cnc(-c2ccncc2)nc1-c1ccccc1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and isonicotinamidine hydrochloride, followed by saponification as described in example 3c) there was obtained 4-phenyl-2-pyridin-4-yl-pyrimidine-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@H:27]2[CH2:31][O:30]C3(CCCCC3)[O:28]2)[N:12]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@H:27]([OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: O=S(=O)(Nc1cc(OC[C@H]2COC3(CCCCC3)O2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cc(OC[C@H](O)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Reaction time: 20 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2S)-1,4-dioxaspiro[4.5]dec-2-ylmethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step ii) (0.34 g) in methanol (5 mL)/H2O (0.1 mL) was added pyridinium p-toluenesulfonate (78 mg) and the mixture was stirred at reflux for 2 h and then ambient temperature for 20 h. The reaction mixture was evaporated, suspended in H2O and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using DCM/MeOH (98:2) as eluent to give the title compound as a white solid. Yield: 0.15 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[C:34]([CH3:35])=[C:33]([CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([CH3:35])=[C:33]([CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1ccnc(C(=O)CBr)c1C
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nccc(C)c2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-3,4-dimethylpyridine hydrobromide*.