Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[NH:10][C:4]=2[NH:5][C:6](=[C:8]=[O:9])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(O)(C)C.CCCCCC>C(O)CCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[C:3]2[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[NH:10][C:4]=2[NH:5][C:6](=[C:8]=[O:9])[N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOc1cc2c([nH]1)NC(=C=O)N=C2Cl
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: CCCCO
Product: CCOc1cc2c([nH]1)NC(=C=O)N=C2Nc1cccc(Cl)c1
Temperature: 50 °C

Procedure:
Under a argon atmosphere, 29.0 g (128 mmol) of 4-chloro-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine and 18.0 ml (171 mmol) of 3-chloroaniline in 430 ml of n-butanol are stirred at 100° C. for 3 h (almost dissolved after≈1 h, then a thick suspension is formed). 400 ml of isopropanol/hexane (1:1) are then added to the reaction mixture cooled to≈50° C., and the product is filtered off and washed with isopropanol and hexane. Stirring in diethyl ether yields 4-(3-chloroanilino)-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine; 1H-NMR (DMSO-d6) 13.0 and 10.53 (2 sb, 2HN), 8.48 (s, 1H), 8.13 (m, 1H), 7.78 (dm, J=8, 1H), 7.76 (s, 1H), 7.45 (t, J=8, 1H), 7.21 (dm, J=8), 1H), 4.37 (q, J=7, 2H), 1.37 (t, J=7, 3H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>CN(C)C=O>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(c1ccc(O)cc1)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
7.85 g (38.4 mmol) of 4-hydroxyphenyl cyclohexyl ketone are heated under reflux for 2 h after addition of 12 g (86.8 mmol) of potassium carbonate and 200 ml of dimethylformamide. 8.54 g (39.9 mmol) of 2-chloromethylquinoline hydrochloride are then added at room temperature. The reaction mixture is stirred at 100° C. for 7 h and subsequently concentrated in vacuo. The residue is taken up in dichloromethane, and the organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo. A column chromatographic purification on silica gel using dichloromethane/methanol (50:1) follows.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C@@H:5]([CH:7]=[O:8])[CH2:4][CH2:3]1.[C:9]([Si](C)(C)C)([F:12])([F:11])[F:10]>>[F:10][C:9]([F:12])([F:11])[CH:7]([C@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[NH:6]1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C[C@@H]1CC[C@H](C=O)N1
Product: C[C@@H]1CC[C@H](C(O)C(F)(F)F)N1

Procedure:
2,2,2-trifluoro-1-((2R,5R)-5-methylpyrrolidin-2-yl)ethanol (Compound 2, Scheme I, R3=methyl) is prepared by oxidation of ((2R,5R)-5-methylpyrrolidin-2-yl)methanol (Compound 4, Scheme I, R3=methyl) to afford the resulting aldehyde, (2R,5R)-5-methylpyrrolidine-2-carbaldehyde (see e.g., Smith et al., March's Advanced Organic Chemistry, 6th ed., Wiley, N.J., 2007, p. 1715-1728). The resulting aldehyde is reacted with CF3-TMS (trimethyl(trifluoromethyl)silane) to afford 2,2,2-trifluoro-1-((2R,5R)-5-methylpyrrolidin-2-yl)ethanol (see e.g., Prakash et al., J. Am. Chem. Soc. 111: 393, 1989).
Reaction SMILES: [F:1][C:2]([F:14])([S:11]([O-:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[Na+:15].[OH2:16]>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:14][C:2]([F:1])([S:11]([O-:16])(=[O:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:8])([CH3:9])[CH3:7].[Na+:15]
Reactant: O
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)[O-]
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)[O-]
Reaction time: 1 h
Yield: 91 %

Procedure:
A glass flask equipped with a thermometer, a condenser and a dropping funnel was charged with 290 g (0.74 mole) of 65% purity sodium 1,1-difluoro-2-(pivaloyloxy)ethane-1-sulfinate, a catalytic amount of sodium tungstate (IV) dihydrate, 600 ml of water, followed by stirring. Then, 170 g (1.5 moles) of 30% oxygenate was added dropwise in an iced bath. After the termination of the dropping, stirring was conducted for 1 hour at room temperature. Then, the termination of the reaction was confirmed by 19F NMR. The reaction solution was concentrated and then rinsed with 500 ml of diisopropyl ether. Subsequently, filtration was conducted and a solid obtained therewith was dried, thereby obtaining 278 g of sodium 1,1-difluoro-2-(pivaloyloxy)ethanesulfonate in the form of a white solid (91% yield, 65% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[Br:15]Br.S([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([Br:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: BrBr
Reactant: O=C(Cc1ccccc1Cl)C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(C(Br)c1ccccc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
2.0 g (9.0 mmole) of 1-(2-chlorophenyl)-3,3,3-trifluoro-2-propanone were dissolved in 30 ml of carbon tetrachloride, and then 0.46 ml (9.0 mmole) of bromine was added to the solution, which was then stirred at room temperature for 10 hours. At the end of this time, sodium hydrogensulfite was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes, after which insolubles were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 10:2 by volume mixture of toluene and ethyl acetate as the eluent, to give 0.87 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(NC(=O)C2CCCCCC2)cc1

Procedure:
4-Cycloheptanecarbonylamino-benzoic acid was prepared as described in Example 3 from 5.55 g (0.0405 mol) of p-aminobenzoic acid and 8.7 g (0.0425 mol) of cycloheptanecarboxylic acid chloride.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>COC(C)(C)C>[Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](OS(C)(=O)=O)C1
Temperature: -5 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Dissolve (-)-cis-3-tert-butyldimethylsilyloxy-cyclopentanol (9.20 g, 42.5 mmol) in anhydrous tert-butyl methyl ether (50 mL) and cool to -5° C. Treat the solution with methanesulfonyl chloride (3.6 g, 46.5 mmol, mesyl chloride), followed by triethylamine (7.2 mL, 51.7 mmol), at such a rate as to keep the temperature between -5° C. and -2° C. with an ice bath. The ice bath is removed and the solution is stirred for 2 hours. The mixture is then transferred to a separatory funnel and treated with brine/water (50 mL/50 mL). The layers are separated and the aqueous layer is extracted with tert-butyl methyl ether (2×50 mL). The organic layer and extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (12.1 g, 97% yield) as a colorless oil; 1 H NMR (CDCl3) δ5.1 (m, 1H), 4.2 (m, 1H), 2.99 (s, 3H), 2.3 (m, 1H), 2.0 (m, 3H), 1.8 (m, 2H), 0.88 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1B(O)O)[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CCOc1ccc(C(F)(F)F)cc1B(O)O
Product: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-ethoxy-5-trifluoromethylbenzeneboronic acid (0.755 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.645 g, 88%). MS=342 (MH)+. 318b) 7-[8-(2-Ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.640 g, 1.87 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.590 g, 2.25 mmol) in a manner analogous to Example 311b to give product (1.06 g, 99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.42 (m, 2H), 7.35 (d, 1H), 7.08 (t, 1H), 7.00 (d, 1H), 4.15 (q, 2H), 3.42 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H), 1.22 (t, 3H): MS=568 (MH)+.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.Cl.S(Cl)(Cl)=O.[NH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:1]12[CH2:8][C:5]([C:9]([NH2:19])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)C12CCCN(CC1)C2
Reactant: N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)C12CCCN(CC1)C2
Yield: 76 %

Procedure:
Ethyl 1-azabicyclo[3.2.1]oct-5-ylcarboxylate (E7, Example 7 hereinafter, 9.6 g, 0.053 mole) was treated with 8M hydrochloric acid (130 ml) and heated under reflux for 18h. The solution was concentrated in vacuo to give a white solid, which was treated with thionyl chloride (80 ml) and heated under reflux for 6h. The reaction mixture was concentrated in vacuo to leave a red semi-solid, which was suspended in dichloromethane (120 ml), cooled in an ice bath and treated with an excess of ammonia/dichloromethane solution. The mixture was stirred at room temperature for 1h, then treated with saturated potassium carbonate solution. The organic layer was separated and the aqueous was extracted with chloroform (3×70 ml). All the organics were combined, then dried (Na2SO4) and concentrated in vacuo to give the title compound (D20) as a brown solid (6.2 g, 76%), which was used without further purification.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:13]([NH:23][S:24]([C:27]2([CH2:30][CH:31]=[O:32])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[C:14]2[O:22][CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]=1[CH3:18]>C1COCC1.CO.C(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:13]([NH:23][S:24]([C:27]2([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[C:14]2[O:22][CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]=1[CH3:18]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)c2n(c1=O)CCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO)CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
Sodium borohydride (0.1 g, 2.6 mmol) was added to a stirred solution of 1-(2-Oxo-ethyl)-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.12 g, 0.21 mmol) in THF (5 mL) and MeOH (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated under reduced pressure and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (2-4% MeOH in DCM) afforded 70 mg of the product (58% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=2)[N:10]=1.Cl.Cl.[NH2:20][CH:21]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:23]([CH2:24][CH2:25][CH2:26]2)[CH2:22]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:29]1[CH:23]2[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:28][CH:21]([NH:20][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:10][C:9]=13)=[O:17])[CH2:22]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3cccs3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cccs4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
A mixture of 2-thiophen-2-ylbenzoxazole-4-carboxylic acid (64 mg, 0.26 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (70 mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99 mg, 0.52 mmol) and 1-hydroxybenzotriazole (99 mg, 0.74 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.17 mL, 1.3 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and then recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamide (55 mg, 56%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=7.0 Hz, 1H), 8.20 (dd, J=7.5, 0.5 Hz, 1H), 7.95 (dd, J=4.0, 1.0 Hz, 1H), 7.67-7.63 (m, 2H), 7.45 (t, J=4.0 Hz, 1H), 7.27-7.23 (m, 1H), 4.62-4.56 (m, 1H), 3.15-3.09 (m, 2H), 2.67-2.59 (m, 2H) 2.54 (s, 3H), 2.18-1.88 (m, 3H), 1.65-1.57 (m, 5H); MS (ESI+) m/z 382 (M+H); HPLC>99% (AUC), tR=24.24 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.BrC[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CN(C)C=O>[CH3:2][C:14]1[CH:13]=[CH:12][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: c1ccc2[nH]cnc2c1
Solvent: CN(C)C=O
Product: Cc1ccccc1C#N

Procedure:
Using the procedure of Step B of Example 1, 951 mg of benzimidazole and 1.97 g of 4-bromomethyl benzonitrile in dimethylformamide were reacted to obtain 2.48 g of crude product which was chromatographed on silica (eluant: methylene chloride-methanol (95-5)) to obtain 1.34 g of the desired product melting at 94° C. after Crystallization from ether. An analytical sample was prepared by two successive crystallizations of 422 mg of the product from ether, then from isopropyl ether to obtain 167 mg of pure product melting at 94° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:13]=[C:12]2[C:23]([NH2:25])=O>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:13]=[C:12]2[C:23]#[N:25]
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
Phosphorus oxychloride (9.6 ml, 103 mmol) was added dropwise, via a pressure equalising funnel, to a cooled (5-10° C.) solution of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide (20.0 g, 68.3 mmol) in dimethylformamide (200 ml). Following complete addition of phosphorus oxychloride the reaction was left to stir for 10 mins before warming to room temperature and allowing to stir for a further 30 mins. The reaction mixture was then poured carefully into ice cold water (2000 ml), the resulting precipitate filtered off and washed with water. The filter cake was then dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting solid was crystallised from diethyl ether to yield 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbonitrile (12.9 g, 46.9 mmol) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][CH3:20])[N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.Cl>[Cl:16][C:15]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][CH:6]=2)=[N:11][C:12]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][CH3:20])=[N:13][CH:14]=1
Reactant: CCC(CO)Nc1ncc(Cl)c(-c2ccc(C(=O)OC)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CO)Nc1ncc(Cl)c(-c2ccc(C(=O)O)cc2)n1
Reaction time: 72 h

Procedure:
4-[5-Chloro-2-(1-hydroxymethylpropylamino)-pyrimidin-4-yl]-benzoic acid methyl ester (68 mg, 0.20 mmol) was dissolved in 4 mL THF. To this solution 41 mg of lithium hydroxide monohydrate in 2 mL water was added and the reaction mixture stirred for 3 days. The reaction mixture was diluted with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 4-[5chloro-2-(1-hydroxymethylpropylamino)-pyrimidin-4-yl]-benzoic acid as a yellow solid, 64 mg, 0.20 mmol. LCMS ES+=322.1.
Reaction SMILES: CC1N(S(O)(=O)=[O:7])C(=O)C1.C(N(CCCC)CCCC)CCC.ON1C2C=CC=CC=2N=N1.[CH:34]1([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:41]([NH:40][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:7]
Reactant: CC1CC(=O)N1S(=O)(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)-](1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>ClCCl>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([S:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-ol (0.050 μg), N,N-dimethylformamide (2.0 mL), potassium carbonate (0.059 g) and bromoacetic acid methyl ester (0.031 g) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane and this solution was washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as brown solid, 0.11 g.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.[ClH:21]>C(OCC)(=O)C>[ClH:21].[C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cnccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cnccc1-c1ccccc1
Reaction time: 1 h

Procedure:
Methyl 4-phenylnicotinate [cp. Heterocycles 22, 151-157 (1984)](53 g, 0.25 mol), 5N aqueous NaOH solution (100 ml) and methanol (100 ml) are refluxed together with stirring for 1 h. The reaction solution is allowed to cool, acidified with concentrated HCl to pH 4 and evaporated to dryness in vacuo. The residue is slurried in hot ethanol (75 ml), filtered, and the filtrates are evaporated to dryness in vacuo. The residue obtained is slurried in cold ethyl acetate (30 ml), filtered and dried to give 4-phenylnicotinic acid hydrochloride, m.p. 239°-241°.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10](C(OC(C)(C)C)=O)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1.ClC1C=CC=CC=1CSC1C=CC2N=C(C3C=CC=CN=3)N(C(OC(C)(C)C)=O)C=2C=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[CH:27]=[CH:26][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2cc(SCc3ccccc3Cl)ccc21
Agent: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2ccc(SCc3ccccc3Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccccc1CSc1ccc2[nH]c(-c3ccccn3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To stirred solution of tert-butyl 5-(2-chlorobenzylthio)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (or the isomer, tert-butyl 6-(2-chlorobenzylthio)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate) (18 mg, 0.04 mmol) in methanol (2 mL) was added 4M HCl in dioxane (1 mL, 4 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by reverse phase preparative HPLC to give 5-(2-chlorobenzylthio)-2-(pyridin-2-yl)-1H-benzo[d]imidazole (2TFA) (8.8 mg, 38%).
Reaction SMILES: [CH3:1][Ge:2]([CH3:16])([CH3:15])[C:3]1[CH:4]=[C:5]([C:9]2([CH3:14])OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O>[CH3:15][Ge:2]([CH3:1])([CH3:16])[C:3]1[CH:4]=[C:5]([C:9](=[O:10])[CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(c2cccc([Ge](C)(C)C)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cccc([Ge](C)(C)C)c1

Procedure:
A mixture of 351 mg (1,25 mmol) of 2-(3-trimethylgermylphenyl)-2-methyl-1,3-dioxolane, 47 mg (0.187 mmol, 0.15 eq) of pyridinium p-toluenesulfonate (PPTS), 1.1126 g (62.5 mmol, 50 eq) of water and 10 ml of acetone was refluxed for 2.5 hours. The reaction mixture was evaporated and extracted with petroleum ether. The extract was evaporated. The oily residue was purified by column chromatography to give 294 mg of colorless oily substance.