Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[Br:22].C(N(CC)CC)C>ClCCl>[Br:22][C:11]1[CH:12]=[C:13]([N:16]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:1](=[O:3])[CH3:2])[CH:14]=[CH:15][C:10]=1[O:9][CH3:8]
Reactant: COc1ccc(NCC(F)(F)F)cc1Br
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(CC(F)(F)F)C(C)=O)cc1Br
Yield: 53.1 %

Procedure:
Acetic anhydride (1.26 ml, 13.4 mmol) was added to a cooled (0° C.) solution of 2-methoxy-5-(2,2,2-trifluoroethylamino)bromobenzene (Description 56, 2.1 g) and triethylamine (1.9 ml, 1.37 g, 13.4 mmol) in dichloromethane and the mixture was heated under reflux for 18 h. The mixture was cooled and the solvent was evaporated under reduced pressure. 1,2-Dichloroethane (20 ml) was added and the mixture was heated under reflux for 24 h. Further acetic anhydride (0.6 ml) and triethylamine (0.95 ml) were added and the mixture was heated under reflux for 24 h., cooled and diluted with dichloromethane (100 ml). The mixture was diluted with water (3×50 ml) and brine (50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate and the solid was collected and dried in vacuo to give the title compound as an off-white solid (1.28 g, 59%). 1H NMR (360 MHz, CDCl3) δ7.44 (1 H, d, J 2.5 Hz), 7.17 (1 H, dd, J 8.7, 2.5 Hz), 6.93 (1 H, d, J 8.7 Hz), 4.29 (2 H, q, J 8.8 Hz), 3.94 (3 H, s), and 1.90 (3 H, m), m/z (ES+) 326, 328 (M+1).
Reaction SMILES: [F:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.Cl.[CH3:22][O:23][NH2:24]>S(Cl)(Cl)=O>[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:2]([F:1])([CH3:6])[C:3]([NH:24][O:23][CH3:22])=[O:5])=[CH:8][CH:9]=1)(=[O:16])=[O:15]
Reactant: CC(F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CON
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CONC(=O)C(C)(F)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A suspension of 1 (0.5 gr, 1.6 mmol) in thionyl chloride (5 mL) was refluxed for 3 h. After cooling at room temperature, thionyl chloride was evaporated under vacuum and the crude acyl chloride was diluted in dry CH2Cl2 (5 mL) and cooled at T=0° C. by ice-water bath. Methoxyamine hydrochloride (0.27 g, 3.2 mmol) was added portionwise. The ice-water bath was removed and the reaction mixture was left stirring at room temperature. After complete disappearance of the starting material (TLC) a buffer solution (pH=2.0) (V=10 ml) was added, the two phases trasferred into a separator funnel and separated and the organic one was washed with brine (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give pure 11 as pale yellow oil (0.47 gr, yield 85%). 1H-NMR (CDCl3) δ 9.05 (bs, 1H, CONH), 7.70 (d, 2H, J=7 Hz), 7.30 (d, 2H, J=7 Hz), 3.80 (s, 3H), 1.95 (d, 3H, J=23 Hz).
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH3:30])C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH3:30])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: CC#CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and but-2-ynoic acid ethyl ester employing the procedure described in Example 95. [α]D25 −33.80 (c 0.5, CHCl3).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][O:1][C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=2)=[O:32])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([O:19][CH2:20][CH3:21])(=[O:18])[C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].N1C=CN=C1>CN(C)C=O>[Si:1]([O:11][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([O:19][CH2:20][CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H](O)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 31.4 g of t-butyldimethylsilyl chloride in 200 ml of dimethylformamide was added dropwise to a solution of 25 g of ethyl (R)-(-)-mandelate and 28.4 g of imidazole in 600 ml of anhydrous dimethylformamide, and the resulting mixture was stirred overnight at 40° C. The dimethylformamide solvent was then removed by distillation under reduced pressure, and the residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:10 by volume mixture of ethyl acetate and hexane as the eluent,. The title compound was obtained as a liquid, boiling at 129° C./3.5 mmHg (466 Pa) by distillation in vacuo. [α]D23 -40.8° (c=1.07, chloroform)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3(OCC[O:13]3)[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]>C1COCC1.Cl.C(OCC)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)CC(=O)CC2
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A solution of 7′-ethynyl-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)naphthalene] (0.85 g, 3.9 mmol) in THF (15 ml) and 1N HCl (5 ml) was stirred overnight at room temperature. Concentrated HCl (2×0.5 ml) was then added in two aliquots 2 hours apart. After stirring a further 2 hours the solution was diluted with diethyl ether, the aqueous phase was separated, and the solution dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (15 g) eluting with diethyl ether:hexane (1:9→1:4) to give 7-ethynyl-2-tetralone as a solid (0.31 g). 1H NMR (CDCl3, 200 MHz) δ: 2.54 (t, J=7 Hz, 2H, CH2), 3.05 (s, 1H, ethynylH), 3.06 (t, J=7 Hz, 2H, CH2), 3.56 (s, 2H, CH2), 7.18 (d, J=8 Hz, 1H, Ar), 7.26 (s, 1H, Ar), 7.34 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].S=[C:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1>C(O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][NH:1][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1
Reactant: CC(C)(O)CN
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CC(C)(O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 1-amino-2-methylpropan-2-ol (2.61 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3 g), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated, and the residue was washed with ethanol to give the title compound (3.90 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](O)=[O:15].S(Cl)([Cl:24])=O.CN(C)C=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([Cl:24])=[O:15]
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)O)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid (6.0 g.), thionyl chloride (7.5 ml.) and dimethylformamide (0.2 g.) in benzene (50 ml.) is heated under reflux for 10 minutes. The mixture is evaporated, benzene (20 ml.) is added and the evaporation repeated twice. Light petroleum (b.p. 40°-60° C., 150 ml.) and carbon are added to the residue, and the solution is filtered and evaporated to give (±)-2-(2-naphthylmethoxy)- 3,3,3-trifluoro-2-methylpropionyl chloride (5.35 g.) m.p, 39°-43° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=O)=[CH:4][C:3]=1[F:33].Cl>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:28]([F:30])([F:31])[F:29])[C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:33]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 25 °C
Yield: 29.5 %

Procedure:
Borane tetrahydrofuran complex (13.05 mmol, 1.26 mL, 1.121 g) was added to a solution of (4-amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (1.043 mmol, 0.5 g) in tetrahydrofuran (8 mL) under nitrogen and the reaction heated to reflux for 5.5 hours. 5M Hydrochloric acid (10 mL) was added and the reaction was heated to reflux for 30 minutes, and then was cooled to ambient temperature. The product was extracted into dichloromethane (50 mL), washed with water (3×50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC affording the title compound (0.143 g). MS (ESI) m/z 466.0 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN)nc1
Reactant: O=C(O)c1[nH]c(-c2cccs2)cc1-c1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3cccs3)cc2-c2ccc(F)cc2)nc1
Yield: 91 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrole-2-carboxylic acid and methyl 6-(aminomethyl)nicotinate hydrochloride, yielding the title compound. Methyl 6-[({[3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]nicotinate: Yield 91%; m.p. 174-176° C.; IR 3378, 3245, 1723, 1618, 1505, 1433, 1218, 1113, 843 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.45 (sb, 1H), 8.95 (s, 1H), 8.21 (dd, J=8.1 Hz, J′=2.1 Hz, 1H), 7.48 (dd, J=8.6 Hz, J′=5.4 Hz, 2H), 7.31-7.23 (m, 2H), 7.21 (d, J=3.6 Hz, 1H), 7.15 (t, J=8.6 Hz, 2H), 7.06 (dd, J=5.0 Hz, J′=3.7 Hz, 1H), 6.88 (tb, J=4.6 Hz, 1H), 6.40 (d, J=3.0 Hz, 1H), 4.65 (d, J=5.0 Hz, 2H), 3.96 (s, 3H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 165.9, 162.9, 161.0, 157.9, 150.0, 142.4, 138.7, 138.3, 136.7, 130.8, 128.6, 128.0, 127.6, 127.2, 122.6, 122.4, 119.3, 116.2, 116.0, 109.1, 51.5, 48.7.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[H-].[Na+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH2:23]([O:1][CH2:2][CH2:3][N:4]1[C:5](=[O:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13])[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOCc1ccccc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of 126 (5 g, 26 mmol) in DMF (50 mL) was treated with sodium hydride (1.1 g, 32 mmol, 70% dispersed in mineral oil) for 30 minutes at room temperature, followed by addition of BnBr (6.7 g, 39 mmol). After additional 1 hour, the reaction was quenched by water (200 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layer was washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 10%-20% ethyl acetate in petroleum ether to afford 127 as a white solid (4.8 g, 65%). (ES, m/z) [M+H]+ 282.0; 1H NMR (300 MHz, CDCl3) δ 7.85-7.88 (m, 2H), 7.71-7.74 (m, 2H), 7.25-7.31 (m, 5H), 4.55 (s, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.74 (t, J=6.0 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([SH:7])([CH3:6])[CH3:5].Br[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>CN(C=O)C>[C:4]([S:7][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)SCc1ccc(C#N)cc1
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
Add sodium hydride (359 mg, 14.21 mmol) to a solution of 2-methyl-2-propanethiol (900 mg, 9.98 mmol) in anhydrous DMF (15 mL) under nitrogen. Stir the mixture for 15 min, add 4-bromomethyl-benzonitrile (2.348 g, 11.97 mmol) and stir the resulting mixture overnight at room temperature. Add water and extract the aqueous phase twice with EtOAc. Wash the combined organic extracts twice with iced-water, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc 92:8 to give the desired intermediate (1.42 g, 69% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][NH:27][CH2:26][C@@H:25]1[NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>ClCCl>[C:43]([N:27]1[CH2:28][C@@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])[CH:14]=3)[N:19]=2)[C@@H:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH2:26]1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: C=CC(=O)N[C@H]1CNC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CN(C(C)=O)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.37 g, 0.76 mmol) in dichloromethane (15 mL) at 0° C. was added DIEA (0.16 mL, 0.92 mmol) and acetyl chloride (0.054 mL, 0.76 mmol) and the reaction was stirred for 60 mins. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((3S,4R)-1-acetyl-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.207 g, 51%). MS (ES+) C25H25Cl2N5O4 requires: 529, found: 530.
Reaction SMILES: C(OC([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.Cl.C(O)(C(F)(F)F)=O>O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(Sc3cccc(C(=O)O)c3)ccc2O1)C[C@H](O)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(Sc2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
To 670 mg (1.25 mmol) of crude 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid (Example 173) diluted in 5 mL 1,4-dioxane, was added 0.5 mL of 6N hydrochloric acid slowly. The resulting mixture was stirred at 45° C. for 2 hours. After this time the mixture was concentrated in vacuo, dissolved in 2 mL of 1:1 methanol to water, and purified by HPLC (0-70% acetonitrile/0.1% TFA) to afford 28.5 mg (5% yield) of the desired product as the bis TFA salt. MH+ 437.3. 1H NMR (CDCl3, δ): 8.91 (br. S, 1H), 8.63 (d, 1H), 8.56 (dd, 1H), 7.89 (m, 1H), 7.72 (dt, 1H), 7.62 (m, 1H), 7.49 (m, 1H), 7.39 (m, 1H), 7.31 (m, 1H), 7.27 (m, 1H), 7.24 (dd, 1H), 6.90 (d, 1H), 6.35 (br. S, 1H), 5.07 (m, 1H), 4.48 (m, 1H), 3.32 (m, 4H), 3.16 (m, 1H), 2.78 (m, 2H), 2.04 (m, 1H), 1.71 (m, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[CH:25][N:24]=[N:23]1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:22]1[CH:26]=[CH:25][N:24]=[N:23]1)([O-:14])=[O:13]
Reactant: c1c[nH]nn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnn3)cc2c1=O
Yield: 25 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1H-[1,2,3]triazole according to the GPB affording 8.5 mg (25%) of a white powder. Rt=4.5 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])#[N:2].[H-].[Na+].[F:10][C:11]([F:27])([F:26])[CH2:12][N:13]=[C:14]([NH2:25])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18](S(C)=O)[N:17]=1>C(O)(C)(C)C>[F:27][C:11]([F:10])([F:26])[CH2:12][N:13]=[C:14]([NH2:25])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[N:17]=1
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: N#CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: N#CCCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 2 h
Yield: 67.2 %

Procedure:
4-Cyanobutanol (10 g.) was added to sodium hydride (2.75 g.) in t-butanol (95 ml.) and the solution warmed to 40°. 4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (11.24 g.) was added over 10 minutes and the solution kept at 40° for 2 hours then at room temperature for 18 hours. The solvent was removed under vacuum and the residue washed with water, then ether to give 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valeronitrile (8.5 g.), m.p. 134°-136°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.[C:13]([NH:16][CH2:17][C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:17][C:18]1([CH3:19])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:20]1)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:15])[CH3:14]
Reactant: CC(=O)CNC(C)=O
Reactant: SCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tryptophol (3.86 g; II, R2, R3, R4, R5, R6 = H and X1 =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only be melting. Rf values of the amide and tryptophol are equal.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=1[NH2:23]>>[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]2[C:15]=1[N:23]=[C:2]1[NH:3][C:4]3[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=3[N:6]1[C:17]2=[O:18]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Cc1cc2nc(Cl)[nH]c2cc1C
Product: Cc1cc2[nH]c3nc4c(C)cccc4c(=O)n3c2cc1C

Procedure:
4,8,9-Trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 3-methylanthranilic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH2:11]([Mg]Br)[CH3:12].C1COCC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:11][CH3:12])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(O)c1c(Cl)ncnc1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Charge 4,6-dichloro-pyrimidine-5-carbaldehyde (2.5 g, 1.0 eq) and toluene (50 mL) in a round bottom flask. Cool the reaction mass to −10° C. Add ethyl magnesium bromide (3M) in THF solution (5.1 mL, 1.1 eq) drop wise at −10° C. Slowly allow the reaction mass to come to RT in 1 h. Charge chilled ammonium chloride solution to the reaction mass and extract with diethyl ether. Wash ether layer with saturated aq. sodium chloride solution. Dry the ether layer over anhydrous sodium sulfate and concentrated it under reduced pressure to get the desired product (2.3 g, 79.3%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1>OS(O)(=O)=O>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Conc. HNO3 (79 mL) was dropwise added to a solution of 4-fluoro-benzoic acid (70 g, 0.5 mol) in conc. H2SO4 (500 mL) at 0° C. The mixture was stirred for 4 h at RT and then poured into ice-water (3.0 L). The precipitate was filtered off, washed twice with water (0.5 L) and dried to give the title compound as a white solid. 1H-NMR (300 MHz, CDCl3): δ (ppm) 11.0 (s, br, 1H), 8.86 (m, 1H), 8.42 (m, 1H), 7.47 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[I:9]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:8][C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([I:9])=[CH:6][N:5]=1
Reactant: II
Reactant: Nc1ccnc(Cl)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Silver sulfate (7.1 g, 22.8 mmol) and 4-amino-2-chloropyridine (4.06 g, 31.6 mmol) were added to a solution of iodine (5.65 g, 22.3 mmol) in ethanol (100 mL) and the reaction mixture stirred at rt for 72 h. The bright yellow suspension was filtered, washed with methanol and the filtrate concentrated in vacuo. The residue was partitioned between saturated Na2CO3 solution (200 mL) and ethyl acetate (200 ml). After separation the organic layer was washed with Na2S2O3 solution (50 mL, 25%) and brine (50 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with iso-hexane/ethyl acetate (3:1 to 2.5:1) to give the title compound. δH (CDCl3): 4.81 (2H, br s), 6.63 (1H, s), 8.38 (1H, s); m/z (ES+)=254.86 [M+H]+; RT=2.51 min.