Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1nc([C@@H](C)N)n2-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c1nc([C@@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 2 (100 mg, 0.398 mmol), 6-chloro-9H-purine (68 mg, 0.438 mmol) and DIPEA (83 μL, 0.478 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 100° C. for 20 h. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in cyclohexane affording 109 as a brown solid (62 mg, 42%) LCMS: RT 3.17 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.18-8.06 (2H, m), 7.95-7.86 (1H, m), 7.66-7.45 (5H, m), 7.11-7.00 (2H, m), 6.86 (1H, d, J=7.81 Hz), 5.49 (1H, br), 2.56 (3H, s), 1.57 (3H, d, J=6.84 Hz)
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[C:10]([F:24])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>CO>[F:1][C:2]1[C:11]([CH2:12][NH2:13])=[C:10]([F:24])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1c(F)cc2ncccc2c1F
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1c(F)cc2ncccc2c1F
Yield: 88.4 %

Procedure:
To a solution of 2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1,3-dione (5.10 g, 15.73 mmol) in CH3OH (150 mL) was added hydrazine monohydrate (0.50 g, 15.73 mmol). The solution was heated at reflux for 3 h. After cooling, the mixture was filtered through celite. The filtrate was concentrated in vacuo. EtOAc was added to dilute the residue, filtered and concentrated in vacuo to afford (5,7-difluoroquinolin-6-yl)methanamine (2.70 g, 88%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.93 (d, 1H), 8.38 (d, 1H), 7.59 (d, 1H), 7.43 (m, 1H), 4.12 (s, 2H). LCMS (method B): [MH]+=195.0, tR=0.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12]C)=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[Na+].CCCCCC.CCOC(C)=O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Cl)c(C=O)cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(Cl)c(C=O)cc1O
Temperature: 65 °C

Procedure:
2-Chloro-4,5-dimethoxybenzaldehyde (5.00 g, 24.9 mmol; commercially available from Akos Consulting) is dissolved at room temperature in conc. H2SO4 (23 mL; Riedel) at room temperature. The deeply colored mixture is heated at 65° C. overnight with stirring, and after cooling is poured with caution into ice-water containing 38 g of solid NaOH (pH 14). The water phase is washed twice with AcOEt, and then is adjusted to pH 1 by addition of HCl 37% with ice-cooling to form a white suspension. Extraction with AcOEt, drying of the organics over MgSO4 and evaporation gives the crude product in a mixture with unreacted starting material. The title compound is obtained after silica gel chromatography (hexane/AcOEt gradient from 3:1 to 1:1) as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.35. MS: 187.0 [M+H]+. ]+. 1H-NMR (DMSO-d6): δ 3.41 (s, 3H), 7.14 (s, 1H), 7.45 (s, 1H), 9.83 (s, 1H), 10.2 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18]Br)[CH:14]=[C:13]([Br:20])[C:12]=2[Br:21])[CH:9]=1)[C:5]#[N:6].[NH3:22].CO>ClCCl>[NH2:22][CH2:18][C:15]1[C:16]([F:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:12]([Br:21])=[C:13]([Br:20])[CH:14]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)c(CBr)cc(Br)c2Br)c1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(CN)cc(Br)c2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A mixture of 3-chloro-5-{[2,3-dibromo-5-(bromomethyl)-6-fluorophenyl]oxy}benzonitrile (0.185 g, 0.371 mmol) and 7M ammonia in methanol (5 mL, 35.0 mmol) in dichloromethane (5 mL) was stirred at RT overnight. The solvent was evaporated and the residue was purified by chromatography (MeOH:dichloromethane) to give the desired product (37 mg, 19.5%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.80 (d, 1H), 7.52 (t, 1H), 7.25 (t, 1H), 7.20 (d, 1H), 3.82 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CCN(CC)CC.OS([O-])(=O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COC(=O)C(C)(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
Methyl 2,2-dimethyl-3-hydroxypropionate (1.32 g), tert-butyldimethylsilyl chloride (1.8 g), 4-dimethylaminopyridine (122 mg) and NEt3 (1.67 ml) were dissolved in DCM (100 ml) and stirred for 16 h at RT. A NaHSO4 solution was added, and the org. phase was further washed with water, dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/4) afforded 800 mg of the desired compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)S(=O)(=O)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)S(=O)(=O)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-6-(N-phenylmethanesulphonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.[CH2:19]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](Br)[CH:30]=1)(=[O:28])=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:17]#[C:16][C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:18])[CH:30]=1)(=[O:28])=[O:27])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cc2ccccc2)cc1Br
Product: Cc1ccc(S(=O)(=O)Cc2ccccc2)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 4-(benzylsulfonyl)-2-bromo-1-methylbenzene (Intermediate 69), the title compound was obtained as a yellow solid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][C:15]([CH3:17])=O.[OH:18][C:19]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>FC(F)(F)C(O)=O>[OH:28][C:25]1[CH:26]=[CH:27][C:19]2[O:18][C:15]([CH3:17])([CH3:14])[O:22][C:21](=[O:23])[C:20]=2[CH:24]=1
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(O)ccc2O1
Temperature: 55 °C
Reaction time: 23 h

Procedure:
10 mL of trifluoroacetic anhydride and 4 mL of acetone were added to a slurry of 2,5-dihydroxybenzoic acid (available from Aldrich) (2 g, 13 mmol) in 16 mL of trifluoroacetic acid. The mixture was stirred at 55° C. for 23 h and then at 85° C. for 2.5 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, dissolved and re-concentrated from toluene twice, and dried under vacuum. The crude solid was dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate solution and once with brine. The organic fraction was dried over sodium sulfate and concentrated. Crude product was purified by column chromatography (eluting from silica gel with a gradient of 5 to 50% ethyl acetate in hexanes) to provide the title product as a yellow solid 0.47 g. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.43 (d, J=2.8 Hz, 1H), 7.08 (dd, J=9.0, 3.1 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 5.45 (s, 1H), 1.71 (s, 6H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[C:15]([Cl:28])[N:14]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:16]=[C:15]([Cl:28])[N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Clc1ccn2c(Br)cnc2c1
Reactant: CC1(C)OB(c2cc(Cl)nc(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccn2c(-c3cc(Cl)nc(Cl)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo[1,2-a]pyridine (1 eq, 3.02 mmol, 700 mg) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.1 eq, 3.32 mmol, 1.01 g) are dissolved in DME (4 ml) and water (1 ml) and Na2CO3 (1.5 eq, 5.53 mmol, 562 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.3 mmol, 212 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 7-chloro-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=299
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)\[CH3:25])=[CH:17][CH:18]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C/C(=C\c1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and benzyl chloride there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid benzyl ester of melting point 113°-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:24]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1ccc(COC2CCCNC2)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC(OCc3ccccc3)C2)ccc1Br

Procedure:
2-Bromo-5-chlorosulfonylbenzoic acid is reacted with 3-benzyloxypiperidine by the method of Example 1. Recrystallization from ether-hexane, yields the product, m.p. 177°-178° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[F-:19].[Cs+]>C1S(=O)(=O)CCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][F:19])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CF)n1
Temperature: 100 °C

Procedure:
To a solution of 2,4-diamino-6-bromomethyl-5-(2,4-dichlorophenyl) pyrimidine (1.04 g) in tetramethylene sulphone (4.5 ml) was added cesium fluoride (1 g). The mixture was stirred and heated at 100° C. for 4 hours, cooled, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (silica; 19:1:0.1 dichloromethane/methanol/triethylamine) to give the title compound, which was recrystallised from ethanol. 0.19 g, mp. 210°-211° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C1COCC1.C1(C)C=CC=CC=1>[Br:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:16]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(Br)ccc1C(=O)O
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Ethyl chloroformate (5.00 ml, 52.1 mmol) was added to a solution of 2-amino-4-bromobenzoic acid (3.75 g, 17.36 mmol) in THF (70 ml) at room temperature. The mixture was heated to 70° C. and let stir for 24 hrs. The reaction was concentrated to give an oily solid. The resulting solid was diluted with toluene (50 mL), concentrated and then triturated with 5% ether/hexanes (100 mL) to give upon filtration and subsequent washing of the solid with hexane the title compound (4.6 gm, 92%) as a solid. LCMS (ES+) m/z 287.88 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[H-].[Na+].[CH2:15](I)[CH3:16].O>CN(C)C=O>[CH3:10][C:6]1([CH3:9])[O:5][CH2:4][C:3]([CH2:11][O:12][CH2:15][CH3:16])([CH2:2][OH:1])[CH2:8][O:7]1
Reactant: CCI
Reactant: CC1(C)OCC(CO)(CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCC1(CO)COC(C)(C)OC1
Reaction time: 2 h

Procedure:
To a stirred solution of 5,5-di-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane (5.0 g) (Beilstein 19, II, 93) in dry dimethylformamide (50 ml) under nitrogen, at 20°, was added sodium hydride (0.68 g, 80% dispersion in oil). The mixture was stirred at 80° for 2 hours and cooled. Ethyl iodide (4.4 g) in dry dimethylformamide (40 ml) was added and the mixture was heated at 110° for 3 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with brine, dried over anhydrous magnesium sulphate and evaporated in vacuo. 2,2-Dimethyl-5-ethoxymethyl-5-hydroxymethyl-1,3-dioxane was obtained as a pale yellow oil (1.2 g) and was used without further purification.
Reaction SMILES: [CH:1]1([CH3:20])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([O:12][CH:13]2[CH2:17][O:16]C(C)(C)O2)=[O:11])[CH2:2]1.[C:21](O)(C(F)(F)F)=[O:22]>>[CH:1]1([CH3:20])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([C:10]([O:12][CH2:13][CH:17]([CH2:21][OH:22])[OH:16])=[O:11])[CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CCC(C(C)C)C(C(=O)OC2COC(C)(C)O2)C1
Product: CC1CCC(C(C)C)C(C(=O)OCC(O)CO)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(p-Menth-3-oyloxy)-2,2-dimethyl-1,3-dioxolan (3 g.) was stirred for 5 minutes at room temperature with 90% CF3COOH (15 ml.), and the CF3COOH removed in vacuo. The residual oil was stirred for 4 hours at room temperature with a solution of K2CO3 (7%) in water:methanol (2:5) (50 ml.). The methanol was removed on a rotary evaporator, water (30 ml.) added and the mixture extracted four times with ether. The combined extracts were dried (MgSO4). Removal of the ether left an oil which was distilled to yield 1-(p-menth-3-oyl)glycerol as a colourless liquid b.p. 135° /0.1 mm.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([O:5][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)OCc1ccccc1

Procedure:
Boc-DL-Pip-OH (2.29 g, 10 mmol) and benzyl bromide (1.79 ml, 15 mmol) were reacted in DMF (20 ml) in the presence of triethylamine (2.1 ml, 15 mmol) to obtain Boc-DL-Pip-OBzl as an oily product. This product was reacted with 2 N HCl/dioxane (5 eq.) for 3 hours to obtain H-DL-Pip-OBzl-HCl.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N:10]1(C(OC(C)(C)C)=O)[CH2:15][CH2:14][CH:13]([C:16]([O-])=O)[CH2:12][CH2:11]1.[OH-].[Na+]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc2oc(C3CCNCC3)nc2c1
Temperature: 0 °C

Procedure:
500 mg 2-amino-4-fluorophenol and 900 mg mono-tert-butyl piperidine-1,4-dicarboxylate are heated in 5 g polyphosphoric acid at 200° C. for 4 h. After cooling the reaction mixture is combined with ice water and made basic with 50% NaOH solution. The precipitate is suction filtered, washed with water and dried. 290 mg (V-8) are obtained as a solid.
Reaction SMILES: [SH:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.Cl[CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH:20]=1>C(O)C>[C:21]1([C:18]2[S:19][CH:20]=[C:16]([CH2:15][S:1][C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[N:17]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Sc1nc2cccc3c2n1CCC3
Reactant: ClCc1csc(-c2ccccc2)n1
Solvent: CCO
Product: c1ccc(-c2nc(CSc3nc4cccc5c4n3CCC5)cs2)cc1
Yield: 93.1 %

Procedure:
A solution of 5,6-dihydro-2-mercapto[4H]imidazo [4,5,1-ij]quinoline (2.04 g, 10.7 mmol) in 1 N-sodium-hydroxide (10.7 ml) and ethanol (10 ml) was treated with 4-chloromethyl-2-phenylthiazole (2.25 g, 10.7 mmol) and the resulting solution heated under reflux for 5 mins. The mixture was concentrated in vacuo and the aqueous mixture extracted with ethyl acetate (2×50 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give a yellow oil which crystallised on trituration with diethyl ether (50 ml) to give the title compound (3.62 g, 93%), mp 116°-118° (Found: C, 66.4; H, 5.0; N, 11.3 C20H17N3S2 requires C, 66.1; H, 4.7; N, 11.6%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:3][OH:4].[N:15]#[C:16]Br>>[F:14][C:11]1[CH:10]=[CH:9][C:8]([S:7][CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)=[CH:13][CH:12]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCSc1ccc(F)cc1
Product: NC1=N[C@@H](CCSc2ccc(F)cc2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(4-fluoro-phenylsulfanyl)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-fluoro-phenylsulfanyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. Colourless oil. MS (ISP): 241.2 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH3:17]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)cc1

Procedure:
4-Hydroxybenzoic acid (10 g) was dissolved in methanol (200 ml.), concentrated sulphuric acid (2 ml.) was added and the mixture boiled under reflux for 18 hours. The resulting mixture was poured into iced water, extracted with 2×100 ml. of diethyl ether, washed with 2×100 ml. saturated sodium bicarbonate solution, 1×100 ml. of water, dried and evaporated to give methyl 4-hydroxybenzoate. The phenolic ester was benzylated using method 1A to give the title compound, m.p. 99°C.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14].C1(C)C=CC=CC=1>O>[Cl-:10].[O:14]=[C:13]1[N:15]([CH3:16])[CH2:6][P+:3]2([CH2:1][N:15]([CH3:16])[C:13](=[O:14])[N:12]([CH3:11])[CH2:4]2)[CH2:8][N:12]1[CH3:11]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C[P+]2(CN(C)C1=O)CN(C)C(=O)N(C)C2
Yield: 88.9 %

Procedure:
A mixture of THPC (19.06 g, 0.1 mol), 1,3-dimethylurea (17.62 g, 0.2 mol), and toluene (150 ml) was heated to reflux in an apparatus fitted with a mechanical stirrer and a Dean-Stark trap for azeotropic removal of the water. The mixture was held at reflux until the evolution of water ceased (4 hr); this condensation, as might be expected, required a longer reflux period and more efficient stirring to displace the last of the water than that of Example 1. Half of the 7.2 ml (100.0%) of water was collected during the first 15 min. The product, which separated during the reaction as a mass of white solids, was broken up, triturated under acetonitrile to remove a resinous by-product (4.09 g), filtered, rinsed with acetonitrile and dried, giving 26.21 g (86.3%) of 3,9-dioxo-2,4,8,10-tetramethyl-2,4,8,10-tetraaza-6-phosphoniaspiro[5.5]undecane chloride (II, R=R'=CH3, X=Cl) as a white, crystalline solid. Two recrystallizations from 2-propanol (12 ml/g) gave pure product, mp 161°-162° C. and resolidifying, then mp 217° C. dec.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[F:16][C:17]1([F:29])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](Cl)=[O:27])[C:19]=2[O:18]1>>[F:29][C:17]1([F:16])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([NH:15][C:13]3[N:14]=[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:3]5[CH:4]=[CH:5][O:1][CH:2]=5)[N:11]4[N:12]=3)=[O:27])[C:19]=2[O:18]1
Reactant: O=C(Cl)c1cccc2c1OC(F)(F)O2
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1cccc2c1OC(F)(F)O2

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (Alpha, 66 mg; 0.3 mmol; 1.2 eq.) as a white powder (75.2 mg, 78%). HPLC, Rt: 4.01 min. (purity 97.4%). LC/MS, M+(ESI): 385.3, M−(ESI): 383.3.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:17]2=[N:16][C:15]=1[CH3:31])=[O:13])(=[O:10])=[O:9])(=O)C.CO.[OH-].[Na+]>C1COCC1>[CH:25]1([CH2:24][O:23][C:22]2[C:17]3[N:18]([C:14]([C:12]([NH:11][S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:10])=[O:9])=[O:13])=[C:15]([CH3:31])[N:16]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NS(=O)(=O)CCCO
Reaction time: 8.5 h
Yield: 34.8 %

Procedure:
To 130 mg of 3-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)sulfonyl]propyl acetate were added 2 ml of methanol, 2 ml of THF, and 1 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring for 8.5 hours. The solvent was evaporated under reduced pressure and to the obtained residue were added water and 1 M hydrochloric acid. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added ethyl acetate and hexane, followed by stirring. The resulting solid was collected by filtration and dried to obtain 41 mg of 8-(cyclohexylmethoxy)-N-[(3-hydroxypropyl)sulfonyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.