Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[CH3:30][CH:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([O:13][C:10]2([CH3:12])[CH2:9][NH:8][CH2:11]2)=[C:27]([CH3:28])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:29]
Reactant: Cc1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1OC1(C)CNC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.024 g, 0.058 mmol) in DCM (2 mL) was added TFA (0.35 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 6) to give 4,7-dimethyl-6-(3-methyl-azetidin-3-yloxy)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale solid (0.008 g, 44%). LC/MS (Table 1, Method 5) Rt=1.913 min.; MS m/z: 317 [M+H]+
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH:32]C(OC(C)(C)C)=O)[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[N:21]=3)[CH:18]=2)=[CH:11][C:10]([CH3:46])=[N:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:46][C:10]1[CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([C:28]5([NH2:32])[CH2:29][CH2:30][CH2:31]5)=[CH:26][CH:27]=4)[N:21]=3)[CH:18]=2)[NH:8][N:9]=1
Reactant: Cc1cc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3c2)n(C(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2ccc3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)n3c2)[nH]n1
Reaction time: 2 h
Yield: 18.7 %

Procedure:
The crude product from Step 1 (79 mg) was dissolved in DCM/MeOH (2 mL/1 mL) and treated with HCl (4 M soln in dioxane, 0.96 mL). The reaction was stirred for 2 hours before it was poured onto ice, made alkaline with dilute aqueous sodium hydroxide solution (2M) and extracted with DCM. The organic phase was washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound (10 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:28][CH3:29])[CH:15]=2)[N:10]=1>C(O)(C)(C)C.CCOCC>[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:28][CH3:29])[CH:15]=3)[N:10]=[C:9]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:18]=2)=[CH:20][CH:21]=1)([CH3:27])[CH3:26]
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Reactant: Oc1ccccc1
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COc1cc2nc(Oc3ccccc3)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
216 mg (2.30 mmol) phenol and 11 mg (0.44 mmol) are dissolved in 2 ml t-butanol and the resulting solution is stirred for 3 h at rt. After that time 80 mg (0.23 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline is added and the solution is stirred at 85° C. overnight. The reaction mixture is diluted with ether and extracted with brine. The organic layer is dried and evaporated. After chromatography (hexane/ethyl acetate the product is obtained as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:22])=[CH:16][C:17]([NH:18][CH2:19][CH2:20]Cl)=[C:12]2[N:11]=[C:10]1[CH3:23].[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:22])=[CH:16][C:17]([NH:18][CH2:19][CH2:20][NH:29][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:12]2[N:11]=[C:10]1[CH3:23]
Reactant: Cc1cc(NCCCl)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Reactant: NC1CCCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(NCCNC2CCCC2)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
Heat a solution of [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl](2-chloroethyl)amine (0.08 g, 0.22 mmol), and cyclopentyl amine (0.2 mL g, 0.22 mmol) in dry NMP (3 mL) at 80° C. for 20 h. Pour the cooled mixture onto water (30 mL) and extract twice with EtOAc (50 mL). Wash the combined extracts with brine (50 mL), dry, and evaporate in vacuo. Purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(OCC)C>[CH3:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccsc1Br
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccsc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 2-bromo-3-methylthiophene (15.0 g, 0.085 mole) and bis(1,3-diphenylphosphino)propane nickel(II) chloride (0.5 g, 0.009 mole) in diethyl ether (75 mL) was cooled to 0° C. Phenyl magnesium bromide (29.6 mL of a 3M solution in diethyl ether) was added slowly, causing the reaction mixture to reflux. After complete addition, reflux was continued for 15 minutes. The mixture was cooled, and approximately 100 mL of an aqueous 10% hydrochloric acid solution was added. The resultant mixture was extracted with diethyl ether, and the extract was washed with an aqueous saturated sodium bicarbonate solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure yielding 17.3 g of 3-methyl-2-phenylthiophene as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([S:16][CH2:15][CH2:14][CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCCSc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCSc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
0.69 g of 4-hydroxybenzaldehyde were dissolved in 30 ml of DMF, and the resultant solution was further added with 0.24 g of 60% NaH while cooling the solution with ice and then stirred for 1 hour after elevating the temperature of the solution to room temperature. Further, the solution was fed dropwise with 1.0 g of 1-chloro-3-phenylthio propane while cooling the solution with ice and then stirred for 1 hour at room temperature and further for a night at 50-60° C. After completed the reaction, the solution reacted was poured into ice-water and extracted with ethyl acetate. The organic layer resulted was then washed with aqueous solution of sodium hydroxide and dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 1.2 g of 4-(3-phenylthiopropyloxy)-benzaldehyde.
Reaction SMILES: C[C:2]1[O:10][C@@H:9]2[C@@H:4]([C@@H](O)[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3NC(C)=O)[C@@H](CO)O2)[N:3]=1.CC(N[C@H]1[C@H](O[C@H]2[C@H](O)[C@@H](NC(C)=O)C(O)O[C@@H]2CO)O[C@H](CO)[C@@H](O)[C@@H]1O)=O.[C:58]([NH:61][C@@H:62]1[C@@H:68]([OH:69])[C@H:67]([O:70][C@@H:71]2[O:79][C@H:78]([CH2:80][OH:81])[C@H:76]([OH:77])[C@H:74]([OH:75])[C@H:72]2[OH:73])[C@@H:66]([CH2:82][OH:83])[O:65][CH:63]1[OH:64])(=[O:60])[CH3:59]>>[CH3:59][C:58]([NH:61][C@H:62]1[CH:63]([OH:64])[O:65][C@H:66]([CH2:82][OH:83])[C@@H:67]([O:70][C@@H:71]2[O:79][C@H:78]([CH2:80][OH:81])[C@H:76]([OH:77])[C@H:74]([OH:75])[C@H:72]2[OH:73])[C@@H:68]1[OH:69])=[O:60].[O:10]1[CH2:9][CH2:4][N:3]=[CH:2]1
Reactant: CC(=O)N[C@H]1[C@H](O[C@H]2[C@H](O)[C@H]3N=C(C)O[C@H]3O[C@@H]2CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Agent: CC(=O)N[C@H]1[C@H](O[C@H]2[C@H](O)[C@@H](NC(C)=O)C(O)O[C@@H]2CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: C1=NCCO1

Procedure:
To prepare trisaccharide oxazoline 3, the 4′,6′-O-benzylidene group in 15 was selectively removed by treatment with 80% aqueous AcOH at 50 C. The resulting compound 21 was then selectively glycosylated at the 6′-OH position with 2,3,4,6-tetra-O-benzoyl-β-D-mannopyranosyl trichloroacetimidate under the catalysis of TMSOTf to give trisaccharide derivative 23 (76%). De-O-benzoylation of 23 with subsequent O-acetylation afforded the O-acetylated pentenyl glycoside 25. Finally, compound 25 was converted to the oxazoline derivative by treatment with NIS/TESOTf to give 26, which was de-O-acetylated to provide trisaccharide oxazoline 3. On the other hand, the known chitobiose oxazoline 6[15] and the LacNAc-oxazoline 7[16] were prepared from O-acetylated N,N′-diacetylchitobiose and N-acetyllactosamine, respectively, following the reported procedure.[15, 16]
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)CCOc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCOc1ccc(F)cc1
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a stirred mixture of 37.6 parts of 4-(4-fluorophenoxy)-2-butanone and 400 parts of ethanol were added portionwise 21.2 parts of sodium borohydride at a temperature below 20° C. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was concentrated to half its volume. After cooling, 500 parts of water were added and evaporation was continued till all ethanol was removed. After cooling, the product was extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated. The oily residue was distilled, yielding 20.80 parts (55.1%) of 4-(4-fluorophenoxy)-2-butanol; bp. 140°-141° C. (water-jet) (intermediate 27).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:22])[CH2:14][CH2:15][C:16]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[C:9]2[NH:8][CH:7]=1)=O)C.[NH3:23]>C(O)C>[NH2:23][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:22])[CH2:14][CH2:15][C:16]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[C:9]2[NH:8][CH:7]=1)=[O:3]
Reactant: CCOC(=O)C1=CNC2=C(C(=O)N(C)C)CCC(C)N2C1=O
Reactant: N
Solvent: CCO
Product: CC1CCC(C(=O)N(C)C)=C2NC=C(C(N)=O)C(=O)N21
Reaction time: 72 h

Procedure:
3.07 g. of 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine are dissolved in ethanol. To the solution a 20% by W/V solution of ammonia in ethanol is added and the reaction mixture is allowed to stand in a closed vessel at room temperature for 3 days. The precipitated crystals are filtered, washed with ethanol. 1.18 g. of 3-aminocarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine is obtained, melting point 220° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:15][CH2:16]1)=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CC[C@H]1CC[C@H](CCO)CC1)C(=O)OC(C)(C)C
Product: CN(CC[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedures described in examples 11.13, 11.14 and 11.15, trans-{2-[4-(2-hydroxy-ethyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester was reacted with methanesulfonyl chloride to give trans-methanesulfonic acid 2-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-ethyl ester, which was subsequently treated with 4N hydrogen chloride in dioxan to yield trans-methanesulfonic acid 2-[4-(2-methylamino-ethyl)-cyclohexyl]-ethyl ester HCl salt as colorless solid; treatment of the trans-methanesulfonic acid 2-[4-(2-methylamino-ethyl)-cyclohexyl]-ethyl ester HCl salt with 4-chloro-benzene sulphonyl chloride then yielded trans-methanesulfonic acid 2-(4-{2-[(4-chloro-benzenesulfonyl)-methyl-amino]-ethyl}-cyclohexyl)-ethyl ester as colorless oil, MS: 438 (MH+, 1Cl).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Br:15])[C:13]=1[CH3:14].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C)C(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:15][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:13]=1[CH3:14]
Reactant: Cc1c(Br)cncc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cncc(Br)c2C)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (1.03 g, 0.89 mmol) and potassium carbonate (8.22 g, 59.5 mmol) were added to a solution of 3,5-dibromo-4-methylpyridine (7.46 g, 29.73 mmol) which was synthesized according to the method described in literature (Gu, Y. G. and Bayburt, E. K., Tetrahedron Lett., vol.: 37, 1966, pp. 2565-2568) and 4-methoxyphenylboronic acid (4.52 g, 29.73 mmol) in a mixture of N,N-dimethylacetamide-water (20:1, 100 ml), and the mixture was stirred at 80° C. for 4 hours. After the temperature of the reaction mixture was set to room temperature and ethyl acetate was added thereto, the insolubles were removed by filtration. The obtained filtrate was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1) to give 3-bromo-5-(4-methoxyphenyl)-4-methylpyridine (3.83 g, yield: 46%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Br)c(N2CCNCC2)n1
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
A solution of 3-bromo-2-chloro-6-picoline (0.2 g), piperazine (0.083 g) and triethylamine (0.096 g) in acetonitrile (5 ml) was heated in the microwave apparatus: 30 min at 120° C. followed by 60 min at 150° C. and 30 min at 170° C. The mixture was concentrated and the product was purified by chromatography (SiO2, CH2Cl2=>CH2Cl2/CH3OH 4:1) to give 1-(3-bromo-6-methyl-pyridin-2-yl)-piperazine (0.05 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([OH:17])=O)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].ON1[C:23]2[CH:24]=[CH:25][CH:26]=C[C:22]=2[N:21]=N1.Cl.C(N=C=NCCCN(C)C)C.C[C@H]1CCCN1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([N:21]2[CH2:22][CH2:23][CH2:24][C@@H:25]2[CH3:26])=[O:17])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)n2c1COCC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester (Comp. No. 5a) (6.09 g, 25.5 mmol) in dimethylformamide (60 ml) was added 1-hydroxybenzotriazole (3.785 g, 0.028 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.37 g, 28 mmol). The mixture was stirred for 1 h at 50° C., then (S)-2-methylpyrrolidine (2.385 g, 28 mmol) was added and the mixture was stirred at 25° C. overnight. Solvents were evaporated, the residue was dissolved in dichloromethane and washed against saturated aqueous sodium hydrogencarbonate to give 7.8 g (100%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 2): Rt=1.06 min; m/z=307.19 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc(F)cc2)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=O)[C:17]([N:19]2[CH2:24][CH2:23][C:22]3([CH2:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[O:25]3)[CH2:21][CH2:20]2)=O)=[CH:8]1>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][N:19]2[CH2:24][CH2:23][C:22]3([CH2:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[O:25]3)[CH2:21][CH2:20]2)=[CH:8]1
Reactant: O=C(C(=O)N1CCC2(CC1)Cc1ccccc1O2)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC1(CCN(CCc3c[nH]c4ccccc34)CC1)O2

Procedure:
A stirred suspension under nitrogen of 1.5 g of lithium aluminum hydride in 150 ml of tetrahydrofuran is treated with a solution of 2,3-dihydro-1'-(indol-3-ylglyoxyloyl)spiro[benzofuran-2,4'-piperidine], Example 22, in 75 ml of tetrahydrofuran according to the procedure of Example 22 to provide a tan solid. The solid is successively recrystallized from an ethyl alcohol-water mixture, chromatographed through a silica gel column with a 2% methyl alcohol in chloroform eluant and recrystallized from ethyl alcohol to provide the product, 2,3-dihydro-1'-[2-(3-indolyl)ethyl]spiro[benzofuran-2,4'-piperidine], mp 167°-169° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:16])([F:15])[S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.I[CH:18]([CH3:20])[CH3:19]>C1C=CC=CC=1>[CH:18]([CH:12]([C:9]1[CH:8]=[CH:7][C:6]([S:5][C:4]([F:15])([F:3])[F:16])=[CH:11][CH:10]=1)[C:13]#[N:14])([CH3:20])[CH3:19]
Reactant: CC(C)I
Reactant: N#CCc1ccc(SC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)C(C#N)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
Fifty percent sodium hydroxide (13.5 ml) is added over a 30-minute period dropwise to a suspension of 4-trifluoromethylthiophenylacetonitrile (9.7 g, 0.045 mol), 2-iodopropane (9.5 g, 0.056 mol), and 18 crown-6 (0.61 g, 0.0023 mol) in 13.5 ml of benzene and the exotherm reaches 43° C. After stirring 2.5 hours at ambient temperature, an aliquot placed on glc shows none of the starting nitrile remaining. The reaction is worked up by adding ice water and extracting with ether, which is washed with 10% HCl, water, and dried over sodium sulfate. Evaporation in vacuo gave 10.2 g (86.8%) of a red-brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.[N-:30]=[N+:31]=[N-:32].[Na+].O>CN(C=O)C>[N:30]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.9 %

Procedure:
A solution of 2-bromomethyl-6-(triphenylmethoxymethyl)pyridine (3.04 g, 6.84 mmol) in DMF (25 mL) was treated with sodium azide (650 mg, 10 mmol) and stirred at room temperature for 20 h. The reaction was poured into water (100 mL), extracted with EtOAc (2×50 mL) and the combined organic phase was washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the product (2.75 g, 99%) as a yellow oil; IR νmax (Film)/cm−1 3060, 2103, 1679, 1594, 1448, 1096 and 706; NMR δH (400 MHz, CDCl3) 4.36 (2H, s), 4.39 (2H, s), 7.20-7.33 (10H, m), 7.49-7.52 (6H, m) and 7.72-7.80 (2H, m)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[O:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)[OH:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.[I-].[Na+].CCOCC>[O:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[O:33][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[OH:26])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(C(O)CCCCCOc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: OC(CCCCCOc1ccccc1)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A mixture of 2-chloromethyl quinoline (1.1 g; 6.3 mmol), 3-(6-phenoxy-1-hydroxyhexyl)phenol (1.8 g, 6.3 mmol) and finely powdered anhydrous potassium carbonate (1.74 g, 12.6 mmol) in acetone (40 ml) containing catalytic amounts of finely powdered, anhydrous cesium carbonate (0.4, 1.3 mmol) and sodium iodide (0.05 g, 0.33 mmol) was refluxed overnight (15 hours). The reaction mixture was cooled to the room temperature and filtered. The solid residue was washed thrroughly with acetone (3×15 ml), and all the filtrates were combined. All volatiles were removed from the combined acetone filtrate to leave a light yellow viscous liquid which solidifed to an off-white solid on trituration with a 1:1 mixture of ether and petroleum ether (35°-55° C.). This solid was chromatographed on silica gel with 35% ethylacetate in hexanes to yield the desired product (1.6 g, 60%) as a white crystalline solid, mp 83°-84.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl>[F:10][C:3]1[CH:4]=[CH:5][C:6]([CH:8]=[CH2:9])=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C=Cc1ccc(F)c(Br)c1
Reactant: C1COCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: C=Cc1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1-fluoro-4-vinyl-benzene (8 g), morpholine (20 mL), Pd2(dba)2 (1.83 g), di-t-butyl-biphenylphosphine (1.2 g), K3PO4 (17 g) in DME (60 mL) was stirred at reflux for 4 h. The reaction mixture was cooled down to room temperature, diluted with methylene chloride, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by Flash Chromatography of Biotage eluting with 7% ethyl acetate in hexanes to give the title compound as an oil (5 g).